Ghosn said it was unlikely that Britain would remove itself from the 28-member EU but, if it did so, Nissan would have to "reconsider its strategy and investments for the future," the BBC reported.
Ghosn said the Nissan plant that employs 6,500 workers in Sunderland, England, is the most productive operation the company has in Europe.
British Prime Minister David Cameron has pledged to put Britain's membership in the EU up for a popular vote by 2017 if his Conservative party wins the general election in 2015, the BBC said.
It is not the first time Ghosn has rattled a sword over Britain's relationship with the rest of Europe. In 2002, he linked the future of the Sunderland plant to Britain's adoption of the euro.
Britons have traditionally been wary of the country linking itself to the European continent, a point underscored by its refusal to adopt the euro. Despite Ghosn's previous threat, however, Nissan has kept the Sunderland plant operating.
Car companies are now desperate for any advantage they can find in Europe, where sales have suffered due to a prolonged recession that has only recently shown signs of abating.