Mark Footitt led the Derbyshire fightback with five wickets, but a superb 179-run partnership between Michael Yardy and Chris Jordan put Sussex in control after Day 2.
Derbyshire were dismissed for 223 in the morning session, as Richard Johnson and Jonathan Clare added 52 runs together before James Anyon broke the stand claiming two in as many balls.
The hosts made an excellent start in reply, as Footitt claimed three early wickets, while Clare (2-58) picked up two, to reduce Sussex to 109-5. But the magnificent stand between Yardy and Jordan (92) ensured that the visitors secured a 105-run lead at the close.
Footitt returned to claim two wickets in the final session to complete an excellent five-wicket haul, as Sussex closed on 328-8, with Yardy unbeaten on 121.
After losing two wickets in the final overs of the opening day, Derbyshire resumed on 158-6 but the hosts lost Ross Whiteley for 12 as he was superbly caught at slip off Jordan.
But Derbyshire recovered well with Richard Johnson and Jonathan Clare sharing an excellent 48-run stand, before the latter was bowled by James Anyon for a quick-fire 25 to move the hosts onto 216-8.
And Anyon would strike again with his next delivery as he bowled Tim Groenewald without scoring, and the Derbyshire innings was ended in the next over as Footitt, who hit Panesar for six with the previous delivery, was caught behind as the hosts were dismissed for 223.
Sussex made a rapid start with Luke Wells hitting consecutive boundaries of Footitt’s opening two deliveries to quickly move onto 23 from 15 balls, but his short vigil was ended soon after as Footitt found an edge that was well caught by Chesney Hughes at second slip.
And it would get even better for the hosts when Footitt claimed his second wicket with a vicious bouncer that Nash miss-timed straight to Clare at square-leg at Sussex entered Lunch on 38-2.
Footitt was amongst the wickets again straight after the restart claiming his third after he trapped Rory Hamilton-Brown lbw for six. Joe Gatting and Yardy began the recovery for the visitors producing a 32-run stand before Clare claimed his first wicket of the match taking a great catch of his own bowling to remove Gatting.
And Clare claimed his second wicket shortly after as Footitt take a superb catch at square-leg to reduce Sussex to 109-5 after 24 overs.
But Yardy and Jordan compiled a magnificent partnership before Tea, adding 103 runs, as Yardy completed his half-century and Jordan was just one short of the feat at the interval with Sussex on 212-5.
The pair continued their impressive stand after the restart, as both batsman raced each other to three figures despite the best effort of the Derbyshire bowlers.
A brief shower forced the players off the field, but it only delayed the duo as first Yardy completed his first century of the season to move Sussex onto 284-5. Before his partner fell eight runs short of the feat as he was caught at slip by Whiteley off Footitt for a career best 92.
And Footitt completed his five-wicket haul shortly after removing Anyon to finish with figures of 5-104, as Sussex closed on 328-8.
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