Reds lock James Horwill will captain the Brisbane-based franchise in Saturday's clash against the Bulls at Suncorp Stadium.
Horwill's frustrating 10-month injury lay-off is set to come to an end when he makes his first appearance since tearing his hamstring on in the Reds' 13-12 victory over the Brumbies in Canberra on May 26 last year.
The Wallabies captain is among five changes made to the starting line-up, along with hooker James Hanson, flanker Jarrad Butler, winger Digby Ioane and centre Anthony Faingaa.
Hanson receives his first starting opportunity of the season following five early season cameos from the bench while Butler replaces the injured Liam Gill, who is expected to miss just one game with a minor knee injury.
After being a match-day withdrawal from last weekend's loss to the Western Force, Faingaa has recovered from a back injury to earn his place in the number 13 jersey.
The Reds also have two potential debutants on their forward-heavy split on the bench with Nigel Ah Wong and Curtis Browning in line to wear the Reds jersey in Super Rugby for the first time.
Reds boss Ewen McKenzie welcomed Horwill back to the side.
"Getting James back on the field has been a long time coming and everyone is extremely excited to see him back after what has been a frustrating 10 months without Rugby," McKenzie said.
"In a perfect world he would have returned sooner if not for an ankle injury he suffered in an unlucky instance at training, but he has handled every challenge thrown at him with class and is now ready to go.
"Unfortunately, we do lose Liam Gill for the match through injury. While we don't consider his injury severe, it's too early in the season to risk putting him out there and ultimately suffering further damage.
"Saia is another that has been battling a neck issue but he has shown us enough during the week to push his way onto the bench. Pleasingly, James Hanson has also been playing very well and he gets his chance in the starting team.
"Digby will no doubt have added motivation this week after missing the Force game while Anthony is also raring to go after being forced to withdraw from last weekend's match on the morning of the game.
"On the bench, Curtis and Nigel have been two guys who have continued to improve at training and make the most of their opportunities in the Reds College XV's three-match program."
Reds: 15 Jono Lance, 14 Chris Feauai-Sautia, 13 Anthony Faingaa, 12 Ben Tapuai, 11 Digby Ioane, 10 Quade Cooper, 9 Will Genia, 8 Jake Schatz, 7 Jarrad Butler, 6 Eddie Quirk, 5 James Horwill (c), 4 Ed O'Donoghue, 3 James Slipper, 2 James Hanson, 1 Greg Holmes.
Replacements: 16 Saia Faingaa, 17 Albert Anae, 18 Rob Simmons, 19 Curtis Browning, 20 Nigel Ah Wong, 21 Nick Frisby, 22 Mike Harris.
Date: Saturday, March 23
Venue: Suncorp Stadium, Brisbane
Kick-off: 19.40 (10.40 SA time; 08.40 GMT)
Referee: James Leckie (Australia)
Assistant referees: Andrew Lees (Australia), Damien Mitchelmore (Australia)
TMO: Steve Leszczynski (Australia)