The former minister – known for his Europhile views – said the prime minister would be taking a “punt” by offering a national vote before negotiations about the EU’s future shape have started.
The comments came in interviews with The Times and Financial Times, ahead of an anticipated speech by Mr Cameron on the union later this month.
Lord Heseltine, an adviser to the coalition on economic growth, insisted: “Mrs Thatcher said ‘Never go into a room unless you know how to get out of it’.
“To commit to a referendum about a negotiation that hasn’t begun, on a timescale you cannot predict, on an outcome that’s unknown, where Britain’s appeal as an inward investment market would be the centre of the debate, seems to me like an unnecessary gamble.”