England wing Sharples has been sidelined since suffering shoulder trouble during Gloucester's Premiership victory over London Irish more than four weeks ago.
But he now returns to take his place in a team that will be captained by former England centre Mike Tindall in France on Thursday night.
Gloucester head coach Nigel Davies has rung the changes following last weekend's Premiership win against Bath, which include first European starts for wing Ian Clark and hooker Koree Britton.
There are also opportunities for the likes of full-back Martyn Thomas, fly-half Tim Taylor and flanker Matt Cox as Gloucester target a winning start in a pool that also includes London Irish and Bordeaux-Begles.
New Zealander Jimmy Cowan, meanwhile, is set for a second successive appearance off the bench after making his debut against Bath.
"Momentum is very important. To continue winning and developing and building our game is really important," said Davies, whose team have gone five games unbeaten in the Premiership.
"We've rotated the squad in the Premiership fixtures already, but it is important that we give an opportunity to some others.
"And we are expecting no less from these guys. They have to step up to the plate and they have to take our game forward."
Mont de Marsan currently prop up the French Top 14 league, having collected just one point all season.
But Davies added: "They are very big, very unpredictable, but very capable.
"If you go out and play French teams and you are accurate and precise, then you have every chance.
"If you don't and it becomes loose and dominated by errors, then they tend to win those games. It's a big challenge for us, a different type of challenge, but an interesting one."
The match kicks off at 7.30pm.
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