Dave Kitson's early red card proved costly as last year's finalists Portsmouth crashed out of the FA Cup, npower League One leaders Brighton running out 3-1 winners.
Pompey have not made it beyond the third-round stage this year after Gus Poyet's men capitalised on Kitson's petulant sending-off to lead 2-0 for much of the game, courtesy of goals from Chris Wood and Ashley Barnes.
Tom Kilbey did pull one back for Portsmouth late on, but substitute Francisco Sandaza soon restored the two-goal margin to secure the Seagulls' place in the fourth-round draw.
Shaun Harrad struck in injury time as Burton caused an upset at the Pirelli Stadium, beating Middlesbrough 2-1 and piling more misery on the Teessiders in the process.
Harrad scored twice in the last 10 minutes as the League Two club came from behind to record a famous victory.
High-flying Norwich are also out after Jimmy Smith's header gave Leyton Orient a 1-0 victory at Carrow Road.
Sheffield Wednesday pulled off a shock win as Gary Teale, Neil Mellor and Clinton Morrison netted in a 3-0 win at Bristol City. Swansea were 4-0 winners over Colchester, while Watford came from a goal down to beat Hartlepool 4-1 and Burnley defeated Port Vale 4-2.
Keiren Westwood saved a penalty as Coventry survived a late fightback to beat Crystal Palace 2-1, while Luke Chambers grabbed a late winner to help Nottingham Forest beat Preston by the same margin.
Elsewhere, Huddersfield claimed a straightforward 2-0 success against Dover and League Two Torquay upset League One Carlisle 1-0.
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