Alistair Darling will accuse Brexit campaigners of offering a "fantasy future" outside the European Union, as he warns that leaving would threaten Britain's long-term economic recovery.
The former chancellor will become the latest political heavyweight to enter the fray in the referendum campaign, saying a vote to leave would signal Britain had become a "country in retreat".
He will draw on his experience at the Treasury at the time of the 2008 crash to underline the economic dangers of uncertainty surrounding Brexit at a time when "dark clouds are gathering on our horizon".
In particular, he will point to the costs of leaving the single market and doubts surrounding the sort of trade deal Britain would be able to negotiate from outside the EU.
He will highlight new research by former cabinet secretary Lord O'Donnell's Frontier Economics consultancy suggesting Britain could lose £92 billion in overall trade if it adopted the "Canadian model" as some Leave campaigners have advocated.
"They are offering fantasy future where we keep all the benefits of being in Europe without being part of the single market. It's Project Fantasy," he will say in a speech in London.
"As a country whose long-term economic recovery relies on the health of our exports and our regulatory environment being attractive to global investors, it would be a colossal surrender of power to walk away from our largest trading partner, increase uncertainty, erect trade barriers and diminish our influence."
After the International Monetary Fund warned that a Leave vote on June 23 could wreak "severe" damage to the UK economy and beyond, Mr Darling will say there is "nothing patriotic about turning a blind eye to credible warnings of economic disaster".
"We know what happens when confidence plummets. We saw that in 2008 and we are still living with the consequences of the global financial crash," he will say.
"Confidence remains low and uncertainty is making that worse. When the IMF single us out as facing what will be a self-inflicted wound, we can't ignore it."
With so much at stake, he will say the wider world is looking at the prospect that the UK could break away from the EU with disbelief.
"If we choose to leave we will survive, but we will send an unequivocal signal that we are a country in retreat. Leaving is not a cost-free, risk-free experiment," he will say.
"The world is watching with incredulity that our country, which has left an indelible mark on history and given the world some its greatest scientific, artistic, intellectual and industrial achievements, is considering choosing to leave rather than lead, choosing isolation over influence."