Guinness Premiership champions Sale Sharks face Leicester, and Ospreys must face Cardiff Blues, with both ties to be staged at the Millennium Stadium on March 24.
Sale Sharks director of rugby Philippe Saint-Andre said: "It's a tough draw but we are looking forward to a great game with Leicester and the day out with our loyal supporters at the Millennium Stadium."
The winners of both ties meet in the final at Twickenham on April 15, and the all-Welsh clash is one Cardiff director of coaching Dai Young believes was inevitable.
"There's no real surprise that we've drawn against the Ospreys and I think most people would have put money on us getting them," said Young.
"However one good thing is that we will definitely get a Welsh representative in the final which will be a big boost to Welsh rugby.
"The players know each other really well and in the context of it being a semi-final of the EDF Energy Cup it looks like being a big occasion for the fans and the players alike.
"The English sides that we've come up against so far had realistic chances of going through and fielded strong teams and now it's at the business end of competition they will be even more focused on that game as it's also a route for them to get in to Europe next year."