Current polls show the Remain camp well in the lead, commanding 55 per cent of support compared with 42 per cent for the Out side.
But Duff, formerly a Liberal Democrat MEP and President of the Union of European Federalists, says a Brexit is still possible.
He says, "Consider, for a moment, what will happen next if the leave camp wins the Brexit referendum. After a raucous weekend, one assumes that the prime minister will make an apologetic statement to the House of Commons on Monday 27 June.
"The next day, leaving Samantha Cameron to begin the packing at No 10, David will make his last appearance at the European Council in Brussels.
"Cameron's reception will be embarrassed. While nobody will want to be seen vindictive, the sense of betrayal among his fellow heads of government will be acute."
Duff, who lost his MEP post after the Liberals were all but wiped out in the last European elections, goes on, "European Commission President Jean-Claude Juncker is already using the language of Britain being in danger of 'deserting' the European cause."
He adds, "Having been forced to undertake an essentially spurious and self-indulgent renegotiation of the UK's terms of EU membership at their February meeting, the European council will now be faced with the convulsion of coping with the UK's secession.
"There will be many regrets but little patience, and great anxiety. The imperative will be to minimise the collateral damage done by the secession to the remaining union, and to prevent contagion of the British disease."
Duff warns, "Brexit will not be made easy."
He says the coincidences of the French and German elections in 2017 reduce the likelihood of any important concessions being made to Britain by François Hollande or Angela Merkel.
"The European Council will wait for Cameron to speak. What will he say? During the referendum campaign he has insisted that 'out is out', and that he would intend, while still Prime Minister, to immediately trigger Article 50 of the treaty on EU in the event of a Leave vote.
"His insistence has been to blunt the claim of certain Brexiteers that recourse to Article 50 is not inevitable and that some ill-defined process less inimical to the interests of the UK can be opened up," he told Policy Network.
Duff, a constitutional expert who was twice re-elected as an MEP, said, "Yet Cameron is correct both legally and politically to stress that there is in fact no alternative to Article 50. The message from the corridors in Brussels is, first, that nobody will react until they hear what Cameron has got to say for himself, but, second, that there can be no new negotiation with the UK outside the parameters of Article 50."
Duff, a visiting fellow at the European Policy Centre in Brussels, added, "Although it is true that Article 50 was meant never to be used, it is also true that it was designed to work in favour of the remaining EU and in disfavour of the seceding state.
"On 28 June, in case Cameron is anything less than crystal clear that the UK has moved into secession territory, Donald Tusk, president of the European council, will be ready to extract from the hapless British prime minister a categorical notification that the game is up. At that point, according to Article 50(4), Cameron will have to leave the room."
He said, "Although UK representatives will be ejected from the Council, British MEPs should continue to sit and vote in the European Parliament until their mandate is extinguished on the entry into force of the withdrawal agreement - probably 1 July 2018.
"So too with Jonathan Hill in the European Commission and the British judges at the Court of Justice: it will be a long, slow withdrawal. And a sad one."
Duff, an MEP from 1999 to 2014, asks, "Could the UK change its mind about leaving the EU, presumably after a general election, at any stage of the Article 50 process?
"Although the treaty is silent on that matter, international convention and common sense would permit the return of the prodigal."