Eoin Morgan and AB De Villiers shared a century partnership before Steven Finn took five wickets as Middlesex completed a Vitality Blast double over local rivals Surrey for the first time since 2008.
Morgan struck 70 off 37 balls - his highest score so far in this year's tournament - while De Villiers, making his final appearance in the South Group, signed off with 64 from 40 as the pair put on 115 in 10.1 overs.
That stand, a Middlesex record for the fourth wicket in T20, set up a 64-run victory for their side - the first time they have beaten Surrey twice in the competition since they lifted the trophy 11 years ago.
Surrey skipper Aaron Finch gave his side hope with a ruthless 25-ball knock of 47 but, once he was out, their batting wilted under pressure as Finn returned career-best T20 figures of 5-16 to dismiss them for 146.
Having lost the toss, Dawid Malan - who had blazed a century when his side triumphed at The Oval a fortnight ago - departed for a third-ball duck as he drove Imran Tahir into the hands of mid-off.
The home side were unable to gain traction in the powerplay, with Paul Stirling leg-before to Tom Curran as he shuffled across the stumps and Stevie Eskinazi run out attempting a suicidal single on the leg side.
But De Villiers and Morgan accumulated runs steadily, with the England one-day captain outscoring his partner as he slammed Tahir for three sixes in a single over.
The third of those took Morgan to his half-century from 27 balls - and De Villiers followed suit in similar fashion the next over, heaving Rikki Clarke over mid-on for a maximum that brought up the hundred partnership.
The stand was eventually broken when De Villiers toe-ended Tom Curran's full-toss to deep midwicket and Morgan, having creamed Jade Dernbach for his fifth six, tried to repeat the shot and was caught on the boundary.
John Simpson, with 18 from just six deliveries, ensured that Middlesex passed the 200 mark and equalled their highest T20 total at Lord's as they closed on 210-8.
However, Finch made his intentions clear as he dispatched Tom Helm's first four deliveries to the boundary and then clobbered Nathan Sowter for two enormous sixes into the Mound Stand.
Helm did pick up the wicket of Will Jacks, bowled off his pads, but Sam Curran went for his shots and helped to ensure that Surrey kept up with the required rate as he and Finch put on a rapid 60.
But Sowter took his revenge on the Surrey captain, luring him out of his crease for Simpson to remove the bails and the wicketkeeper did the honours again when Curran top-edged Finn to depart for 39.
Finn's fiery spell blew the middle order away, with De Villiers holding two catches in the deep as Surrey's last eight wickets went down for 29 runs.