Remaining in the EU offers Wales "huge" tourism and business opportunities, Liberal Democrats leader Tim Farron has argued, launching the Welsh party's campaign for the referendum on 23 June.
He said tourism was worth £6.9bn to Wales, supporting about 206,000 jobs.
Mr Farron said the Liberal Democrats was the only UK party "completely united" on remaining in the EU.
But Prof Patrick Minford, a former advisor to Margaret Thatcher, said the EU was "dysfunctional".
Now based at Cardiff Business School, said it was time for Wales and the UK to leave the union.
Mr Farron visited businesses in Brecon, Powys, with Welsh Lib Dem leader Kirsty Williams on Thursday.
"The EU offers our small businesses and tourism sector huge opportunities, I can't understand why anyone would want to shut those opportunities down," he said.
"Of course we recognise that the EU is not perfect, neither is Westminster. But picking up your ball in a sulk and heading home is not the way to win."
But Prof Minford said: "We are regulated by Europe and our labour market, our industry and our economy is warped by the European protectionist cocoon."