Captain Wayne Madsen top-scored with 45, but Derbyshire's valiant run chase wasn't enough as record-breaking Lancashire claimed a 35-run victory at Emirates Old Trafford.
Ashwell Prince (56 off 29 balls) and Karl Brown (58 off 34 balls) both his half-centuries as the hosts hit a mammoth 225-7 from their 20 overs, the highest Twenty20 score ever made by Lancashire at home.
Derbyshire responded well to their hefty task, scoring at 9.5 runs an over with Madsen (45), Marcus North (41) and Wes Durston (30) all contributing. But the respectable effort was ultimately in vain as Derbyshire closed on 190-7.
After losing the toss and being asked to bowl first, Derbyshire claimed their first wicket in Mark Turner's (3-51) first over, second of the match, as Smith was caught in the deep by Greg Cork for 13.
Karl Brown and Ashwell Prince, however, put on 89 for the second wicket as Lancashire seized control of the game. Prince hit 56 from 36 balls to set the innings up, whilst his partner Brown was equally impressive for his 58 from 47.
The big-hitters continued to come for Lancashire as England international wicketkeeper-batsman Jos Buttler came to the crease to join Brown. Brown and Buttler put on a partnership of 56 before Brown was caught off the bowling of Greg Cork (1-29) to leave Lancashire on 158-3 in the 15th over.
Madsen ran out Steven Croft for four soon after, brilliantly stopping a drive at cover before hitting the stumps directly whilst still lying down.
Academy graduate Ben Cotton, playing in his first competitive game for Derbyshire, took his first wicket for the first-team, and it was a notable one, as Jos Buttler was caught by Billy Godleman for 39. But it couldn't halt the hosts who closed their innings on 225-7.
Durston and North opened up for Derbyshire and got them off to a good start, scoring 50 without loss from the first five overs, which included four sixes, before Durston was first man out for 30 off 20 balls (2 fours, 3 sixes).
Gareth Cross came in and, for the third successive NatWest T20 Blast fixture, played an important quick-fire innings to keep up the momentum in the Derbyshire innings, hitting 17 from 10 balls.
The third wicket to fall for Derbyshire was that of North, who had played nicely for his 41 before being trapped lbw by Steven Croft to leave Derbyshire on 101-3 in the 11 over, still in with a sniff of victory.
Madsen continued to push, hitting 45 off just 25 balls (4 fours, 1 six), but when he fell in the 16th over, with Derbyshire were 156-5, it signalled the end of any slim hopes of an unlikely win.
Derbyshire finished their innings on 190-7 to lose by 35 runs and attentions now turn to Sunday when Derbyshire face Glamorgan at The 3aaa County Ground in the LV= County Championship.
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