The UK could be broken up by a coalition of Tories and nationalists, claims Welsh Secretary Peter Hain.
Both Peter Hain and Gordon Brown warn of the 'Balkanisation of Britain'
Mr Hain says Plaid would damage Wales economically by pursuing independence while Conservatives would harm the union by cutting the role of Welsh MPs.
Opposition politicians have dismissed his comments.
Speaking after Chancellor Gordon Brown also warned of a threat, Mr Hain called for the end of the UK a "one-way street to irrelevance for Wales".
The Neath MP, who wants to be Labour deputy leader, spoke after Chancellor Gordon Brown also warned of the threat.
Mr Brown, who is expected to become prime minister later this year, warned at the weekend of the "Balkanisation of Britain".
In an article for Saturday's Daily Telegraph, the chancellor accused today's Conservatives of adopting "anti-Unionist positions" in collusion with nationalists.
Writing in Monday's Western Mail, Mr Hain said the chancellor's call for a debate on Britishness was "long overdue - not least because the Union is under attack from the Laurel and Hardy partnership of the Tories and the nationalists".
"The contribution of Wales to the industrial development of Britain was enormous, helping to create prosperity and to turn us into a world power.
"In return, Wales has long benefited from support from the Treasury, with Welsh public spending almost £1,000 per head higher than in England.
"Today's booming Welsh economy, with more jobs than ever in our history, 10 years of growth, low interest rates and low inflation, and world-class manufacturing operations like Airbus, would be unthinkable in the event of separation.
"If we are to compete against the likes of China and India in a globalised economy, we must do so together as we have been doing successfully up to now."
Rhodri Glyn Thomas AM, deputy leader of Plaid Cymru in the Welsh assembly, said Mr Hain was trying to "create any concern in people's minds which will salvage a vote for Labour".
He said: "Peter Hain is once again peddling this negative politics. He's gone from the unbelievable - he was talking about a Conservative-led coalition which nobody believes will happen - and now he's gone to the totally absurd. He says a vote for Plaid or the Conservatives would undermine the union. This is ridiculuous."
Mr Hain had said "shared values and interests" were under threat from a coalition of Tories and the narrow separatists of Plaid Cymru and the Scottish nationalists.
"The Tories, despite once priding themselves as 'the party of the Union,' now place selfish party advantage ahead of national interest," he wenton.
"By trying to whip up and then harness nationalist sentiment in England, they risk unleashing forces which can lead to only one thing: the Balkanisation of Britain. That would damage Britain and damage Wales."
Warning against "nationalist introspection" in Wales, he added: "Unless we see it off, it will prove a one-way street to the disintegration of the United Kingdom - and a one-way street to irrelevance for Wales."
William Graham, Conservative AM for South Wales East, said his comments were nothing to do with concern about the UK's future but about fueding within Labour.
He told Radio Wales: "The union is completely safe with the Conservative and Unionist Party."
Observers believe the Union is likely to be a major issue in the Scottish Parliament elections in May, with the Scottish National Party committed to independence.
However, it is likely to have a lower profile in Wales, where Plaid Cymru's stated aim is "to promote the constitutional advancement of Wales with a view to attaining full national status for Wales within the European Union".
On Tuesday, BBC Wales will reveal the findings of a poll it has carried out on the state of the Union