The Welsh side's task looks even more daunting with a host of Welsh internationals, like skipper Alun Wyn Jones, props Adam Jones and Aaron Jarvis, all ruled out with injury.
The Ospreys will have to create their own piece of history at the Stade Ernest Wallon by grinding out their first ever win over the most successful side in the history of the Heineken Cup.
But the Ospreys, who have played Toulouse twice before and lost both games, have won only one of their 11 games in France in the Heineken Cup when the Welsh region recorded a 28-21 victory over Bourgoin back in 2008.
Welsh sides do not have a good record against the four-times Heineken Cup winners on home soil, with only the Llanelli Scarlets managing a victory over Toulouse back in 2006.
Toulouse have lost just one of their 15 homes games against Welsh sides in Europe and will be favourites to get a victory and to qualify for the last eight of this year's tournament.
• Toulouse have lost just one of 15 home games against Welsh opposition in this competition, losing to Llanelli Scarlets back in 2006.
• Conversely Ospreys have won just one of 11 trips to France in the Heineken Cup, a 28-21 victory over Bourgoin in 2008.
• Ospreys are one of just two teams (with Scarlets) yet to steal an opposition lineout in the Heineken Cup this season.
• Alun Wyn Jones has won a competition joint-high 14 line-outs for Ospreys this season.