The outgoing president of the European Commission will today warn David Cameron he could make a "historic mistake" by alienating eastern European countries as he attempts to renegotiate the UK's links with Brussels.
With the prospect of a referendum on leaving the European Union, Jose Manuel Barroso will say that individual countries like the UK could not retain "even marginal relevance" in a globalised world without the combined weight of the other member states behind them.
He will deliver the message after saying yesterday that the Prime Minister's hopes of curbing EU immigration - a central plank of his European strategy - could be illegal.
The Prime Minister has promised to reform the UK's relationship with the EU ahead of an in/out referendum by the end of 2017 if he remains in office after the general election.
Mr Barroso will tell an audience at the foreign affairs think tank Chatham House that the European Commission will "constructively" engage in the discussions - but Mr Cameron will require allies in other EU governments to succeed.
Reports have suggested that Mr Cameron is considering an annual cap on the number of national insurance numbers that could be issued to low-skilled migrants from within the EU.
The NI numbers would only be granted for a temporary period, to prevent new arrivals from other EU nations indefinitely working and claiming tax credits in the UK.
On BBC1's Andrew Marr Show yesterday, Mr Barroso said "any kind of arbitrary cap seems to me to be not in conformity with the European rules because for us it's very important the principle of non-discrimination".
Concerns about EU migration have been driven by the number of people who have come to the UK from the former Soviet bloc countries.
But in his speech Mr Barroso will warn that the argument for reform should not "alienate" those countries, when unanimity is required for changes to the rules.
He will acknowledge there are "widespread concerns in the UK and elsewhere about abuse of free movement rights" and some further changes could be made that would "not put into question this basic right, which cannot be decoupled from other single market freedoms".
He will say: "The Commission has always been ready to engage constructively in this discussion. But changes to these rules need all countries to agree.
"And it is an illusion to believe that space for dialogue can be created if the tone and substance of the arguments you put forward question the very principle at stake and offend fellow Member States.
"It would be an historic mistake if on these issues Britain were to continue to alienate its natural allies in central and eastern Europe, when you were one of the strongest advocates for their accession."
Mr Cameron angered the leadership in Warsaw earlier this year by questioning why the UK should pay child benefits to the children of Polish workers who remained in their home country.
He later reassured his then Polish counterpart Donald Tusk - soon to take over as president of the European Council - that he was not singling out immigrants from his country for criticism over abuse of the UK's benefits system.
In his comments on the "existentialist European debate" in the UK, Mr Barroso will warn that Britain - or any other European nation - could not wield major influence on the world stage alone.
"Just as nearly 70 years ago peace could not be built by one country alone, today even the largest, proudest European nation cannot hope to shape globalisation - or even retain marginal relevance - by itself. It is only together that we have the weight to influence the big picture," he will say.
"Does that mean a relentless march to one single super-state as some would have us fear? For me the answer is a resolute no."
In a reference to the rise of Nigel Farage's Ukip, former Portuguese prime minister Mr Barroso will say: "I may prefer a glass or two of good red wine than a pint of beer when I am out on the election trail.
"But I too come from a country with a long history, a trading nation, proud of its culture and tradition.
"And it may be a revelation to some, but the vast majority of people living in Europe are also rather attached to their national identity - however they may choose to define it.
"I believe that our future is as an ever closer union of the peoples of Europe - acting as sovereign nations to freely pool their effort and power where that can deliver results that are in their own self-interest.
"My experience is that those countries which use European leverage to project their interests globally matter more. Those who are reluctant are missing an opportunity to maximise their influence."
Mr Barroso will say he had not challenged the UK's decision not to adopt the euro or enter the Schengen open borders scheme, as the EU is "strong because it respects diversity".
He will say he does not "underestimate the very real concerns UK citizens are expressing about Europe" but will criticise politicians for not making the positive case for the EU.
"It worries me that so few politicians on this side of the Channel are ready to tell the facts as they are. To acknowledge that in today's world there are some things which we can only do effectively by acting together," he will say.
"My experience is that you can never win a debate from the defensive.
"We saw in Scotland that you actually need to go out and make the positive case. In the same way, if you support continued membership of the EU you need to say what Europe stands for and why it is in the British interest to be part of it."
Warning of the effect on business, he will say: "Over three-quarters of CBI members want the UK to stay in, because they consider the single market is worth between £62 and £78 billion pounds to the economy.
"Five out of six City UK members say they do not want to see the UK leave, and the same is true for manufacturers.
"The Government's own figures show that some three million UK jobs are linked in some way to the single market. And concern is also starting to be expressed by some of your closest international allies, including the US.
"The big question that the UK needs to ask itself is this: are you sure you are better off outside than in? Only the British people can weigh up the pros and cons and decide that. From our side, the door has always been, and will always stay open."