They have never faced each other in European action but the Saints will take confidence from their record at Franklin's Gardens where they have a 79 per cent success rate.
Jim Mallinder has rung the changes for the Pool One the clash with Lee Dickson replacing former Osprey Kahn Fotual'i at scrum-half and Alex Walker coming in for injured Alex Corbisiero, while Jamie Elliot, Phil Dowson and Samu Manoa also start.
The Ospreys were left seething following their home defeat to Leinster in Round One. Alun Wyn Jones described the performance as unacceptable and Richard Fussell has branded Sunday's showdown as a "do or die" encounter.
The Welsh region have failed to reach the knockout stages in Europe in the last four seasons and are already on the back foot but they remain confident of causing an upset in Northampton.
Steve Tandy has made three changes to his side Tito Tebaldi has paid the price for poor decision-making at the Liberty Stadium, with Tom Habberfield handed the scrum-half jersey, while Ryan Bevington and Jeff Hassler also start.
"We are well aware that we need to make some big improvements if we are going to put in the kind of performance at Northampton that we need," said Tandy. "They are in the same boat as us having also lost their first game, so no doubt there'll be a tension and edge to the game.
"This is a very difficult group but there's still everything to play for and there's going to be plenty of twists and turns. We have to show what we are about on Sunday."
Dylan Hartley's front row clash with British & Irish LIons hooker Richard Hibbard will be one of the more interesting personal battles on the day and whichever team gets on top in the front five will probably come away with the points.