"I am sceptical of a great deal of European Union policy but flirting with leaving at a moment when the whole world is coming together seems to me to be very dangerous," Major, Conservative prime minister from 1990 to 1997, told BBC Radio.
"For the United Kingdom, 67 million out of a world population of 7 billion, to break off and head into splendid isolation doesn't seem to me to be in our interests."
Major, 72, said a British exit would increase the chances of another independence referendum in Scotland that could fracture the United Kingdom.
He said the renegotiation effort was important but shouldn't determine whether or not Britain remained in the 28-member bloc, where it would be safer and more prosperous.
Major warned that many of the arguments put forward by those who favour leaving the EU were "illusory" and that quitting the bloc would also not allow Britain to have complete control over immigration, a key voter concern.
"If we leave the European Union it won't be a friendly departure, it'll be very acrimonious, negotiations with an irate ex-partner could be very difficult, we may get a very sub-standard deal to enter the single market," he said.
"In or out we can't keep the world at bay," said Major.
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