David Cameron has warned that quitting the European Union could lead to the "disintegration" of the United Kingdom.
During a speech at the British Museum setting out the case for Britain remaining part of the bloc, Mr Cameron warned that Brexit could fuel a fresh push for Scottish independence.
Noting the UK was in a voluntary union of four nations, the British Prime Minister urged voters to go to the ballot box with their "eyes open".
Scottish First Minister Nicola Sturgeon has said there will be an "almost certain" drive for another independence referendum north of the border if Scotland votes to stay in the EU but England votes to leave.
All of Scotland's major parties are firmly in the Remain camp and support among voters wanting to stay in outnumbers Leave by around two to one.
Mr Cameron said: "Let me just say this about Scotland - you don't renew your country by taking a decision that could ultimately lead to its disintegration. So, as we weigh up this decision, let us do so with our eyes open."
Mr Cameron also warned that Europe's peace could be jeopardised if Britain votes to leave the EU, as he suggests the referendum contest will form a pivotal moment in the continent's history.
The EU contest is entering a new phase, with both sides stepping up their activities in the run-up to the 23 June referendum.
Mr Cameron stressed the long, historic links with continental Europe - and highlighted the sacrifice of British military personnel to ensure the peace of the continent as he made a "patriotic case" for a Remain vote.
PM: Far from Britain’s influence in the world being undermined by our membership of the EU, it amplifies our power.
— UK Prime Minister (@Number10gov) May 9, 2016
He warned that quitting was a reckless and irresponsible economic risk.
The UK must be strong in Europe if it wants to be strong in the world, he insisted, as he praised the EU for reconciling warring countries.
Mr Cameron said: "The serried rows of white headstones in lovingly-tended Commonwealth war cemeteries stand as silent testament to the price this country has paid to help restore peace and order in Europe.
"Can we be so sure that peace and stability on our continent are assured beyond any shadow of doubt?
"Is that a risk worth taking?
"I would never be so rash as to make that assumption."
'Mad' not to leave - Johnson
Blog: How will recent results transfer to Brexit vote?
However, Boris Johnson has said Britain would be "mad" not to take the once-in-a-lifetime chance of voting to leave the EU.
The former London mayor’s comment came in a speech in which he rejected accusations that the Brexit camp were "little Englanders", insisting that withdrawal from the EU will allow the UK to trade and co-operate with its continental neighbours in a spirit of "liberal cosmopolitanism".
Speaking just hours after Mr Cameron warned that Brexit would be a threat to peace and stability in Europe, Mr Johnson insisted that it is NATO that underpins peace, while the EU is "a force for instability and alienation".
Comparing the EU to the Italian mafia, he warned of a campaign of "subterfuge" to hide from the British public constitutional changes which he said were being introduced with the aim of creating "a country called Europe".
The Uxbridge MP - who has become the leading figurehead of the Leave campaign - said that the Remain camp relied on the three "wholly bogus" myths that membership of the EU boosts the economy and helps preserve peace and that a desire to quit the 28-nation union is anti-European.
"I am a child of Europe. I am a liberal cosmopolitan and my family is a genetic UN peacekeeping force," said Mr Johnson, who broke briefly into a German-language rendition of Beethoven's Ode To Joy to prove his point.
"I can read novels in French and I can sing the Ode To Joy in German - and if they keep accusing me of being a Little Englander, I will.
"Both as editor of the Spectator and Mayor of London I have promoted the teaching of modern European languages in our schools. I have dedicated much of my life to the study of the origins of our common European culture and civilization in ancient Greece and Rome.
"So I find it offensive, insulting, irrelevant and positively cretinous to be told - sometimes by people who can barely speak a foreign language - that I belong to a group of small-minded xenophobes; because the truth is it is Brexit that is now the great project of European liberalism, and I am afraid that it is the European Union - for all the high ideals with which it began - that now represents the ancient regime."
