Premier League leaders Manchester United will play second placed Arsenal at Old Trafford in the stand-out tie of the fifth round of the FA Cup.
League One side Huddersfield Town will travel to Stamford Bridge to face last year's winners Chelsea.
Sheffield United manager Bryan Robson will take on former team Middlesbrough while Liverpool will play Championship opposition in Barnsley at Anfield.
League One strugglers Bristol Rovers face Championship side Southampton.
Portsmouth also have Championship opposition when they travel to Deepdale to play Preston, who beat Premier League bottom side Derby 4-1 at Pride Park on Saturday.
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"It could have been a good deal worse," said Portsmouth manager Harry Redknapp, whose side are one of six Premier League teams left in the competition.
"It's a decent draw against a club with great history and I'm looking forward to going up there maybe meeting people like Tom Finney.
"Everyone wants a home tie at this stage but we are quite happy about this.
"We've got a chance because we have our Africa Nations Cup players back and when we're at our strongest I think we can give anybody a game."
And two Championship sides are guaranteed a berth in the quarter-finals as Cardiff City host Wolves at Ninian Park and Coventry City take on West Brom at the Ricoh Arena.
Premier League champions Manchester United have won the FA Cup a record 11 times, while Arsenal have collected the famous trophy on 10 occasions.
The two teams last met in the final in 2005, a match which Arsenal won 5-4 on penalties after a goalless 120 minutes.
Meanwhile Sheffield United will be hoping for another Premier League scalp after their 2-1 victory over Manchester City when they take on Middlesbrough at Bramall Lane.
And Blades manager Robson will come face-to-face with his former club, whom he guided to the 1997 FA Cup final during his six-and-a-half years in charge at the Riverside Stadium.
"It's a very interesting draw. It's one the lads are entitled to think they are in with a chance of winning after beating two Premier League sides already," said Robson.
"Personally, I've still got a lot of good friends at Middlesbrough, including (chairman) Steve Gibson, and it will be nice to see them again."
Fifth round fixtures:
Bristol Rovers v Southampton
Cardiff City v Wolves
Sheffield United v Middlesbrough
Liverpool v Barnsley
Manchester United v Arsenal
Preston v Portsmouth
Coventry City v West Brom
Chelsea v Huddersfield Town
The ties are scheduled to take place on 16 and 17 February.
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