Mayor of London Boris Johnson has said leaving the EU would be a "win-win for all", urging those backing exit to "hold our nerve and vote for freedom".
The EU was an anachronism which "costs us a huge amount of money and subverts our democracy", the Tory MP said.
He insisted there were no downsides to leaving, suggesting the UK could ape Canada's trade arrangement with the EU.
But David Cameron said it was wrong to say the UK could do a "sweetheart deal" with the EU after walking out.
And in his first major intervention in the referendum debate, former prime minister Tony Blair said he was concerned by the "fervour" of those wanting to leave the EU but he believed that the UK would ultimately vote to remain on 23 June as it was in the national interest.
Mr Johnson, one of a number of senior Conservatives to break ranks with the PM and back EU exit, told activists in Kent that the UK was the most creative country in Europe and was "big enough and strong enough to stand on its own".
'Mad and idealistic'
If people were faced with the choice of whether to join the EU in 2016, he said they would probably regard the organisation as "a bit mad and idealistic", with huge "costs and bureaucracy" which restricted nation states' ability to make their own laws and control their borders.
"Would anyone in their right mind want to join the EU today?" he said. "It is 50 years old, it is going in the wrong direction. It is time for real reform. The only way to get that is to leave."
Mr Johnson said the UK could forge a new free trade deal with the EU, based on Canada's existing arrangement, and dismissed suggestions by Prime Minister David Cameron that he and other Leave campaigners were willing to sacrifice jobs and growth to achieve a measure of greater independence.
"You look at the plan to increase the efforts to prop up the single currency with an ever denser system of integration, with more and more regulation about all sorts of social and economic issues which will impact directly on this country, I think the risk is increasingly in staying in the project.
"I think the best thing we can do is show a lead, show an example and strike out for freedom."
Taking a swipe at the campaign to stay in the EU, which opponents have dubbed "Project Fear", Mr Johnson quoted US President Franklin Roosevelt, saying "the only thing we have to fear is fear itself", adding "even fear is not that scary".
Canada has been cited by a number of Leave campaigners as a model for how the UK can continue to do business with the EU without being bound by rules on freedom of movement or having to contribute to its budget.
It signed a free trade agreement with the EU in 2014, seven years after talk about closer economic co-operation was first mooted. The agreement, which eliminates 98% of tariffs between the two blocs, has yet to be ratified by either side but is expected to enter into force next year.
Addressing activists in Wales, Mr Cameron said having to negotiate new trading rules from scratch would lead to a long period of unacceptable uncertainty for British business.
"Seven years of not knowing what the arrangements would be for trading with Europe," he said. "Seven years of uncertainty for businesses wanting to invest in Britain not knowing what our relationship with Britain would be.
"They cannot be justified. They cannot be in our national interest. We should reject that out of hand."
By BBC Political Correspondent Iain Watson
One of the key lines of attack from those who want to remain in the EU is what would "out" look like?
Those who want to leave are taunted that they have no clear idea of what kind of trade deal could be struck with Brussels if we withdraw.
But today Boris Johnson provided the clarity that had been requested - look across the Atlantic to Canada, he said.
So now expect the focus of the Remain attack to change.
Far from being grateful for the London Mayor's clarification, the terms of that deal will be denounced.
Already pro-EU campaigners are pointing out just how long it took for a Canadian agreement to be struck - and are questioning if it'd be appropriate for the UK, which is far more reliant on financial services.
As Boris Johnson will find out, throwing aside his comfort blanket of bluster and giving clear answers to questions in this complex EU debate comes with consequences.
Labour MP Chuka Umunna, who is campaigning to Remain in the EU, said the Canadian model excluded the services industry - which accounts for a huge proportion of British employment - and accused Mr Johnson of "playing fast and loose" with jobs linked to EU membership.
"I am fed up with this entertainment, tomfoolery and the rest from Boris Johnson. This will affect my constituents," he told BBC News.
And Mr Blair told Radio 4's Today that the UK's destiny was to "lead in Europe", warning Brexit would lead to economic instability and "damage fundamentally" the interests of the British people.
"I would like to see the pro-European side get out there with a bit of passion and vigour and determination and stand up for what we believe.
But in a further boost for the Leave campaign, the head of the Conservative group of MEPs in the European Parliament, Syed Kamall, has said he believes the UK "could forge a better life outside" the EU.
Mr Kamall, who also heads the pan-European ECR group, said he believed a "fair and balanced" immigration policy was only possible outside the EU.