Neil Woodford, head of Woodford Investment Management, raised concerns about the growing "economic disparity" between the richer and poorer countries in the bloc and says he is "very conscious of the stresses and strains" within the EU.
David Cameron's Conservative party has promised to hold an in-out referendum on the EU if they win May’s general election.
While Mr Cameron has said that he would prefer to remain part of the EU, he believes this is only viable with the renegotiation of Britain’s agreement with the bloc.
"The likelihood of a referendum, I think, will put a brake on external investment, international investment in the UK… it will create uncertainty," Mr Woodford said in an interview with the BBC."
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"It’s a gut feel that investors will definitely have to impute a higher level of uncertainty with respect to the future of the economy, [and] the currency. All those things will have an effect on investment," he added.
"Ultimately, this country will have to make a choice about whether it is a fully signed-up member of a Eurozone project or not and, I think, sort of being half in as we are at the moment was never really a long-term viable position to be in."
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On top of Britain’s position, Mr Woodford said there were some "fundamental" errors with the EU’s current operation, which have been brought to a head by the victory of the anti-austerity party Syriza in the Greek elections.
"I am very conscious of the stresses and strains that will continue to increase, I think, in the Eurozone.
"The debt problems, the economic disparity – in a very simple sense pretending that Greece was Germany is a fundamental error."
"Pretending that Portugal was Germany… having the same interest rate, the same monetary policy for two economies that are so different seems to be a fundamentally flawed assumption," he said.
Greece negotiated a four-month extension of its loans with the EU last month, but has warned it may leave the Eurozone if the pressures of austerity can’t be lifted.