Perpignan host Toulouse at Barcelona's Olympic Stadium this weekend while leaders Toulon and Biarritz will test their perfect records on the road.
Toulon and Montpellier kick the action off on Friday before Biarritz travel to Castres, who are near-unbeatable at home.
Racing Metro face a tough trip to the Basque country to meet Bayonne while Mont-de-Marsan's winless streak is likely to continue against Clermont's big guns.
Grenoble have been the surprise package of the opening weeks and have a chance to continue their strong start to the season in Agen.
Saturday's late fixture sees Stade FranÃ§ais attempt to remedy their poor form outside of the capital when they visit Bordeaux.
Friday, September 14
Montpellier v Toulon
Saturday, September 15
Perpignan v Toulouse
Agen v Grenoble
Bayonne v Racing MÃ©tro
Castres v Biarritz
Mont-de-Marsan v Clermont
Bordeaux-BÃ¨gles v Stade FranÃ§ais
Rugby Union betting odds
1 Toulon 18
2 Biarritz 17
3 Toulouse 15
4 Clermont 14
5 Grenoble 13
6 Castres 11
7 Racing Metro 10
8 Montpellier 9
9 Stade FranÃ§ais 6
10 Bayonne 6
11 Perpignan 6
12 Bordeaux-Begles 5
13 Agen 2
14 Mont-de Marsan 0
Montpellier HÃ©rault Rugby v Rugby Club Toulonnais
Stade Yves Du Manoir, Montpellier
The weekend kicks off with Round Five's biggest clash as the championship leaders - with Fred Michalak starting at 10 for the first time - head along the Mediterranean coast in search of their fourth win on the road this season.
Such is the depth of the RCT squad that they have the luxury of leaving world-class players such as Gethin Jenkins and Maxime Mermoz on the bench while Jonny Wilkinson is given a rest after hurting his neck last week.
It's a tough assignment then for Montpellier, but les HÃ©raultais have a very strong home record, especially against France's big clubs. The absence of six Pumas is still a concern however.
The battle between Michalak and Francois Trinh-Duc is being billed as the showdown for the France 10 jersey, with Montpellier more likely to play with an open style.
RCT are chasing their first success in Montpellier in seven visits.
Montpellier: 15 Benjamin Thiery, 14 Timoci Nagusa, 13 Thomas Combezou, 12 Shontayne Hape, 11 Yohann Artru, 10 Francois Trinh-Duc, 9 Benoit Paillaugue, 8 Alex Tulou, 7 Mamuka Gorgodze, 6 Fulgence Ouedraogo, 5 Thibaut Privat, 4 Hendrikus Hancke, 3 Vincent Pelo, 2 Erasmus Jansen van Vuuren, 1 Mikheil Nariashvili.
Replacements: 16 Fabien Dorey, 17 Yvan Watremez, 18 Alikisio Fakate, 19 Alexandre Bias, 20 Eric Escande, 21 Pierre Berard, 22 Matthew Carraro, 23 Giorge Jgenti.
Toulon: 15 Alexis Palisson, 14 Vincent Martin, 13 Mathieu Bastareaud, 12 Matt Giteau, 11 David Smith, 10 Frederic Michalak, 9 Sebastien Tillous-Borde, 8 Chris Masoe, 7 Steffon Armitage, 6 Pierrick Gunther, 5 Jocelino Suta, 4 Bakkies Botha, 3 Carl Hayman, 2 Mickael Ivaldi, 1 Andrew Sheridan.
Replacements: 16 Jean Charles Orioli, 17 Gethin Jenkins, 18 Simon Shaw, 19 Nick Kennedy, 20 Maxime Mermoz, 21 Joe van Niekerk, 22 Benjamin Lapeyre, 23 Xavier Chiocci.
Results last season: Montpellier won 18-6 at home; Toulon won 18-6 at home.
Prediction: Montpellier's home record should not be taken lightly but Bernard Laporte's army look unstoppable at the moment. Toulon by a whisker.
Kick-off: 20.50 (18.50 GMT)
USA Perpignan v Stade Toulousain
Estadi OlÃmpic de MontjuÃ¯c (Barcelona)
The defending champions travel to Spain for an extra-long road trip that manager Guy NovÃ¨s says they could have done without.
Nevertheless Perpignan are pushing forward with their plan to spread the rugby word to their Catalan neighbours south of the border at the 55,000-seater Olympic Stadium in Barcelona, although USAP president Paul Goze is only expecting a crowd of between 25-30,000.
"The conditions are not the same as in 2010," Goze said of the 52,000-strong crowd that witnessed Biarritz's Heineken Cup quarter-final against Toulon in April of that year.
"It's not a knock-out match, it's less easy to attract people, the economic crisis is there and yet more in Spain."
Toulouse will, however, take comfort in the fact that they won't be visiting Stade AimÃ©-Giral, where they have won just twice in 17 games.
The added pressure of a gala game at a new venue probably isn't what Perpignan need right now as they languish in the bottom quarter of the standings.
While Toulouse have the best attacking stats in France at the moment, USAP have just one victory to their name, an unconvincing success over Bayonne last week.
Young Toulouse prop, Antoine Guillamon, won't make the trip because of a back injury but centre Florain Fritz should make his return.
Former Wasps wing Richard Haughton has been included in the USAP squad.
Results last season: Perpignan won 25-10 at home; Toulouse won 21-17 at home.
Prediction: Current form points to a win for the champs, especially considering Perpignan's front row injuries. Toulouse by six points.
Kick-off: 15.00 (13.00 GMT)
SU Agen v FC Grenoble
Stade Armandie, Agen
Agen are in spot of bother. Still without a win after four rounds, another defeat this weekend would be cause for panic.
After getting a spanking in Toulouse last week, the hosts must lift themselves for a battle with a Grenoble side that is defying the predictions by lying fifth in the standings thanks to big wins over Mont-de-Marsan last week and Stade FranÃ§ais the week before.
Agen have won four of their last five home games against Grenoble, but are they in the kind of form needed this weekend?
Previous results:Agen won 22-16 at home (ProD2, 2009); 12-12 draw in Grenoble (ProD2, 2009).
Prediction: Agen are a better side than their results so far suggest. Agen by six points.
Kick-off: 18.30 (16.30 GMT)
Aviron Bayonnais v Racing-MÃ©tro 92
Stade Jean Dauger, Bayonne
Two sides that came close to victory on the road last week but had to settle for losing bonus-points face off in what is set to a be an intriguing battle.
Racing came agonisingly close to ending Clermont's three-year winning streak at home and looked very impressive. The Parisians are facing a crisis at fly-half, however, with both Jonathan Wisniewski and Benjamin Dambielle ruled out with long-term injuries while Juan Martin Hernandez is away on international duty with the Pumas.
Centre Fabrice Estebanez and scrum-half Mathieu BÃ©lie are potential solutions in the interim.
Bayonne pushed Perpignan hard but came up short last week, leaving them with just one win this