A similar result in Scotland would be a big blow to Steve Tandy and co prior to a two-week break in domestic competition, especially as they have to face Glasgow and second-placed Leinster in two of their following three games.
Their form on the road in the RaboDirect PRO12 has been impressive this season, though, with defeats at Munster and Ulster their only failings in seven away trips.
And they will take more confidence from the fact that they were easy winners when the two sides met in Swansea in mid-September. The 2005, 2007, 2010 and 2012 champions scored six tries in a convincing 44-10 success as they picked up maximum points in Round 3.
But Edinburgh have improved greatly since then and have a decent record on home soil this term, with the Scarlets and Glasgow the only sides to leave with a league win. Alan Solomons' side have beaten the Dragons, Treviso, Zebre and Leinster at Murrayfield, with Munster and Perpignan also falling short there in the Heineken Cup.
And the Ospreys have not enjoyed much success in the Scottish capital in recent seasons, either, with a 15-14 win during the 2011/12 campaign their solitary victory in their last six visits.
Friday's fixture will break new ground for both clubs, however, with the game being played at Meggetland rather than Murrayfield. The home of Boroughmuir will host the first Edinburgh game to be played away from the national stadium for almost a decade as the Murrayfield pitch is given extra time to recover from a parasitic infection.
Wales fly half Dan Biggar starts for the Ospreys as Tandy makes a host of changes to his starting line up. In the backline, Tito Tebaldi joins Biggar at halfback, Hanno Dirksen comes in for Aisea Natoga on the wing and Richard Fussell replaces Sam Davies at full back, with only captain Jonathan Spratt, Ashley Beck and Jeff Hassler retaining their places from last weekend.
Up front, there is a return to regional action for Wales openside Justin Tipuric in place of Sam Lewis, while Tyler Ardron moves from second row to blindside and loanee lock Perry Parker is promoted to a starting spot against his parent club.