Vittorio Missoni and his wife were among six people on board the flight from the archipelago of Los Roques towards Caracas' Maiquetia airport.
The small, twin-engine aircraft disappeared mid-morning local time on Friday and has not been traced since.
Mr Missoni, 58, is the son of the founder of the eponymous brand and co-owns the firm with his siblings.
He was returning from a Christmas and New Year holiday with his wife, Maurizia Castiglioni, and two friends - Elda Scalvenzi and Guido Foresti. Two Venezuelan pilots were also on board.
The family confirmed that the plane was missing on Saturday.
"The Missoni family has been informed by the Venezuelan consulate that Vittorio Missoni and his wife are missing, but we don't know any more," said spokeswoman Maddalena Aspes.
She added that the authorities, who called off the search after nightfall, were expected to resume it in the morning.
Los Roques, an archipelago made up of dozens of islands some 95 miles (150km) off Venezuela's coast, is one of the area's most popular holiday destinations.
According to the Corriere della Sera newspaper, the pilot of the twin-motored Britten Norman BN2 Islander plane, dating from 1968, was 72-year-old German Merchan.
Another plane with eight Italians on board is reported to have disappeared exactly five years ago, on 4 January 2008. Only a single body - that of the co-pilot - was ever found.
A small aircraft carrying the director of Italian fashion house Missoni has disappeared off the coast of Venezuela.