Neil Dexter led the Middlesex attack as he claimed six Lancashire wickets on the first day of the LV= County Championship Division One clash at Lord's.
Jos Buttler and Tom Smith both hit half-centuries as the visitors mounted a middle-order comeback before they were eventually bowled out for 266.
Dexter, more noted for his batting prowess, returned career-best figures of 6-63 after Middlesex won the toss and put Lancashire in to bat.
The visitors lost opener Paul Horton for just 12 early on after he was caught at second slip by Ollie Rayner off Toby Roland-Jones to leave the visitors 19 for one.
— Middlesex Cricket (@Middlesex_CCC) May 11, 2014
His opening partner Luis Reece started confidently and hit two consecutive fours off Roland-Jones in the 12th over before losing his wicket for 23 to a catch behind by John Simpson off Tim Murtagh.
The wickets continued to fall as Dexter claimed his first victim, bowling Karl Brown for 25 and striking again two overs later as he trapped Ashwell Prince lbw for 17 to leave the visitors struggling on 83 for four.
The Red Rose were 92 for four at lunch and in great need of a strong partnership, with Luke Procter and Buttler at the crease.
Buttler was dropped at second slip in the afternoon session, just before the visiting side passed the 100 mark.
The pair mounted a decent recovery as they took the score to 138 with a fifth-wicket partnership of 55 before Procter lost his wicket, caught at second slip by Rayner off Dexter.
Tom Smith reaches 50 http://t.co/rNWffiNc3F
— Lancashire CCC (@LancsCCC) May 11, 2014
Buttler reached his second Lancashire half-century off 85 balls - which included eight boundaries, two of them in succession off fellow England hopeful Steven Finn in the 52nd over.
Smith and Buttler, with 59, put on a sixth-wicket partnership of 43 before the latter became Dexter's fourth victim just before tea, captain Chris Rogers with the catch at extra-cover to leave Lancashire 181 for six.
Glen Chapple was the next to fall for 26, caught by Roland-Jones for Finn's first wicket of the day, before Smith celebrated his 50 and then Kyle Hogg, on 18, was trapped lbw by Dexter.
The last two wickets - that of Simon Kerrigan, who became Dexter's sixth victim of the day, and Smith, who was bowled by Finn for 59 - fell for just six runs as Lancashire posted 266 all out before stumps were drawn.