Table topping Hampshire overcame Derbyshire's challenge thanks to Adam Wheater's quick-fire 70 and Sohail Tanvir's three wickets on his competition debut at the Ageas Bowl.
In reply to the Yorkshire Bank 40 champions daunting 277-8 after being put in, Derbyshire could only muster 231-8 as they stumbled to a 46-run defeat.
Hampshire, who won both limited-overs trophies last season, have now won five of their six matches in Group B of the YB40 and at the halfway mark are in a strong position to qualify for the knockout stages.
Michael Carberry led the way when Hampshire batted with 53 before he was caught down the leg side by wicketkeeper Richard Johnson off David Wainwright.
When Neil McKenzie was spectacularly caught by the diving Mark Turner, Hampshire were 137 for five in the 26th over and in need of inspiration.
They got it from Wheater and Liam Dawson in a spectacular stand of 84 in nine overs for the sixth wicket until Dawson edged Jonathan Clare to Shivnarine Chanderpaul.
But Wheater was by now in his stride, taking 21 in an over from Turner including two sixes and also hitting Clare for six on his way to his best score since joining Hampshire from Essex in the close season.
Wainwright bowled Wheater sweeping in the penultimate over but the damage had been done as inexperienced Derbyshire lost control.
Turner was punished for some short deliveries by conceding 75 from his eight overs but he also produced another brilliant catch to dismiss James Vince and ran out Jimmy Adams from backward point.
Derbyshire needed the best part of seven an over to stand any chance of winning but they scored too slowly to threaten Hampshire's dominance seriously.
Paul Borrington and Chanderpaul put on 51 for the third wicket but were out in successive deliveries - Chanderpaul run out by Adams - and Hampshire easily shut out their toiling opponents.
Wayne Madsen (43) and top scorer Dan Redfern, who made 53 from 48 balls, did their best to retaliate in a stand of 89 for the fifth but in 14 overs it was not quick enough.
Redfern was last out at 218, bowled by Sohail with only three overs left and Hampshire already celebrating victory.
All-rounder Sohail dismissed opener Chesney Hughes in his second over and returned to get rid of Clare and Redfern as Derbyshire tried to accelerate, finishing with figures of three for 42.