Challenge Cup holders Wigan Warriors will play Castleford Tigers in the quarter-finals while Bradford Bulls will face Warrington Wolves on home soil.
Wigan, who beat Hull FC 16-0 in last year's final at Wembley, coasted into the round after easing past Hunslet Hawks, however, Castleford will pose a much harder test.
Daryl Powell's Tigers have already beaten Wigan once this season and their Super League victory over Wakefield Wildcats means they are currently second in the standings.
Powell said: "It's a tough draw but we've had it pretty comfortable so far with a couple of Championship sides, so you can't complain too much when you get a difficult one.
"If you're going to win something you have to beat good sides. We'll go there with a bit of confidence. We've beaten Wigan the last two times we've played them, so there's no reason to fear it too much. We just need to go and play.
"There's a bit of time before the game so you don't know what the form line of both teams is going to be at that point, but our form is good.
"We feel that we've got a chance no matter who we are playing this season. It's a one-off game."
Castleford's Michael Channing Tweeted: "Wigan away, tough draw for the quarters, will be a good game for us!"
The Bulls' reward for upsetting Catalan Dragons in the fifth round is another home clash, although the Wolves, who dispatched Doncaster 68-0, will pose a much sterner test.
Super League leaders Leeds Rhinos have unusually been paired against a lower league side after being drawn against Leigh Centurions at Headingley.
The Rhinos dumped St Helens out with a 32-12 scoreline on Saturday and will be the favourites to reach the final four against Leigh, however, the Centurions are unbeaten this season and scoring points for fun.
Rhinos full-back Zak Hardaker, who bagged two tries against Saints, Tweeted: "Always good when you get a home tie.. Leigh at home is going to be a tough one."
Widnes ended Marwan Koukash's dream of taking Salford to Wembley this season with a 30-20 win over the Red Devils and up next is a Cougars team who edged out Swinton 33-20.
Draw in full:
Wigan v Castleford
Leeds v Leigh
Bradford v Warrington
Widnes v Keighley
Ties to be played on the weekend of June 7-8.
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