Nick Clegg accused Ukip of running a campaign based on "false claims and fear" as he warned that millions of jobs would be put at risk if the UK left the European Union.
The Deputy Prime Minister said Nigel Farage's party was "two-faced" to suggest that immigration resulting from European Union membership could threaten British jobs.
He said it was inevitable that unemployment would rise if the UK severed ties with Brussels because of the number of firms which depend on trade with Europe.
Mr Clegg said: " The most disingenuous thing of all is to somehow claim that they are standing up for British jobs because, if you actually did what Ukip want, which is to pull us out of the world's largest economy, the one thing that would happen - like night follows day - is that there would be more unemployment in this country."
The Liberal Democrat leader, who was widely considered to have lost two head-to-head debates with Mr Farage ahead of next month's European elections, said Ukip claimed they were " standing up for British jobs when they actually want to destroy British jobs".
Mr Clegg said Labour and the Tories, under Ed Miliband and David Cameron, had "refused to make the case" for European membership, with the Lib Dems claiming this was for fear of losing voters to Ukip.
But he said that on visits to factories including car plants and "metal bashing" industries in his Sheffield constituency he was often reminded of the importance of European trade.
"Why would you then say to those people who are in work 'We are going to put your jobs at risk' in pursuit of some dogma which I think would destroy our prosperity rather than increase it?"
Ukip's controversial poster campaign has been described as racist by some critics but Mr Clegg declined to use the term on his LBC Radio phone-in show, saying: "The words I would use is that they are based on falsehoods, they are based on false claims and fear."
As the Lib Dems launched their European campaign, he added: "Spreading fear is no way to lead this country and certainly no way to have an honest debate about what's at stake at these European elections."
The Lib Dems have also indicated that they would refuse to prop up a minority government after the next general election, potentially paving the way for another term in coalition if there is no clear winner at the 2015 contest.
Cabinet minister Danny Alexander said a minority administration - where a party tries to govern without an absolute majority in the Commons - would not be good for the economy.
Speaking to the BBC, Mr Alexander said: "I believe a minority government, an unstable government, without its own majority to carry its programme would not be in the British national interest.
"It would not be in the national interest because a minority government would not be able to take the difficult decisions that will still need to be taken in the next parliament to keep our economy on track."