Brentford came back from two goals down to take Premiership Southampton back to Griffin Park on March 1.
The Saints seemed to be cruising into the last eight when Henri Camara was twice left with easy tap-ins to score.
But Brentford threw themselves a lifeline when Isaiah Rankin was allowed to cut in from the left and fire across former Bees keeper Paul Smith.
The comeback was completed when Jay Tabb stood a tempting cross up at the far post for Sam Sodje to head home.
Despite a vital looming Premiership match with West Brom, Saints boss Harry Redknapp gambled on fielding a three-pronged strike force in Kevin Phillips, Camara and Peter Crouch.
Phillips made a quick impact on his return to first-team action, thrusting at the Brentford defence before slipping a neat reverse pass to Graeme Le Saux, whose low cross provided Camara with a simple tap-in.
But that early goal failed to shake Brentford out of their stride and Smith denied his old team with a fine point-blank save from Deon Burton.
Southampton's celebrations were short-lived
Southampton had the edge in quality in the first half and Calum Davenport almost doubled their lead with a powerful header from Le Saux's well-flighted corner.
Harry Redknapp's men were partially handed the cushion of a second goal by Bees keeper Stuart Nelson.
Phillips again played a part, initially unwittingly when Nelson whacked a clearance into the back of his head.
The ball broke for Peter Crouch who fed Phillips and when Nelson could only parry his shot, Camara was on the spot to tap home.
But Brentford shook Southampton out of their comfort zone five minutes before the break when Rankin was allowed to cut in from the left touchline and fire his shot across Smith.
If Saints bossed the first half, Brentford certainly had the better of the second and Michael Dobson typified Brentford's spirit by haring back to get in a goal-saving tackle on Phillips.
That spirit deservedly got Brentford back in the game when Tabb stood the ball up for Sodje to head home from close range.
Nelson redeemed his error for Southampton's second goal as Saints mounted a late siege, with a brilliant save from Crouch's header.
Southampton manager Harry Redknapp:
"We really could have done without a replay, but we're in it and we have to get on with it.
"When you go 2-0 up at home against a lower division team you're entitled to feel you should win the game but we have to defend better than we did.
"It should have been game over but the goal before half-time gave them a lift and we took our foot off the pedal."
Brentford boss Martin Allen:
"I don't even know when the replay is. We've got important games against Hartlepool and Sheffield Wednesday to come first.
"But we're in the hat for the sixth round, which is very exciting and keeps the bank manager happy.
"It showed the players'character and I thought we could have won it."
Southampton: Smith, Delap, Lundekvam, Davenport, Le Saux (McCann 68), Prutton, Oakley, Bernard, Camara, Crouch, Phillips.
Subs Not Used: Poke, Telfer, Jakobsson, Higginbotham.
Booked: Le Saux, Prutton.
Goals: Camara 4, 36.
Brentford: Nelson, Dobson, Turner, Sodje, Salako, Tabb (Harrold 89), Hutchinson, Frampton, Talbot, Burton (Hunt 81), Rankin (May 75).
Subs Not Used: Fitzgerald, Lennie.
Goals: Rankin 40, Sodje 58.
Referee: G Poll (Hertfordshire).