Sussex captain Ed Joyce scored his sixth LV= County Championship hundred of the season before a late comeback by Lancashire's bowlers kept the Division One match at Hove evenly poised.
Joyce passed 1,000 runs for the season and 15,000 career runs in a chanceless 137, his seventh first-class century of the summer.
Chris Nash, who made 67, helped him put on 156 for the second wicket and Joyce and Craig Cachopa took Sussex to 247 for two before Lancashire, who realistically need to win to avoid relegation, hit back by taking five wickets for 56 runs.
Chris Jordan and Ashar Zaidi steadied the ship in an unbroken eighth-wicket stand of 38 as Sussex closed on 341 for seven, a lead of 21 runs after two days.
Lancashire made the ideal start when James Anderson squared up Sussex opener Luke Wells with the third ball of the day during an excellent seven-over burst with the new ball in which he was unlucky not to take further wickets.
Lancashire struggled to support the England seamer, and with Tom Smith's six overs before lunch leaking 43 runs, Joyce and Nash were able to establish their partnership.
It had reached 156 from 43 overs when Nash, who struck 11 fours in his 67, tried to loft left-arm spinner Simon Kerrigan's eighth ball and was caught by Glen Chapple at mid-on.
Joyce, however, never gave a chance as he advanced to the 38th first-class hundred of his career which he reached with a pull for four in front of square off Chapple.
Cachopa had a reprieve when Jos Buttler missed a straightforward stumping chance but played solidly for his half-century, adding 90 in 25 overs for the third wicket with his captain before Anderson returned for a fourth spell after tea and had Cachopa caught behind pushing forward.
Luke Wright got off the mark with a six over long-on off Kerrigan and it was a surprise when Joyce was well caught by the diving Steven Croft at backward point off Smith, having hit 18 fours in 203 balls faced in four and three-quarter hours.
Chapple immediately brought Anderson back for the second new ball and it did the trick as Sussex lost three wickets for 10 runs.
The Lancashire captain had Wright taken at second slip and Ben Brown caught behind for a duck before Mike Yardy was run out by Usman Khawaja's direct hit from the covers when Jordan called him through for a single.
That left Sussex 303 for seven but Jordan and Ashar Zaidi survived a tense final hour to take them into the lead.
Joyce's seventh first-class hundred of the season was extra special as it was the first time he had scored a century in front of his father James.
He revealed: "My dad and my elder brother Johnny come over every season to see me play in a couple of games and that's the first time I have made a hundred in front of them so that was a nice moment.
"Lancashire have got two high quality bowlers - Jimmy Anderson is probably the best bowler in the world - and we knew the second new ball would be crucial. I got out just before it was due which was annoying.
"They bowled and caught well but we have a lead and three wickets left and hopefully we can extend that in the morning."