Jack Straw has said a referendum on the EU constitution will take place "early in 2006" if Labour wins a third term.
The prime minister and foreign secretary were in Rome to sign the constitution
The UK foreign secretary was speaking on the day EU leaders signed the new constitution in Rome.
He said it would be impractical to hold the vote in 2005 when the UK would be holding the EU presidency.
Ministers say the constitution is necessary to speed up decision making in an enlarged EU. Tories argue it would be "bad for Britain".
Not the last?
Prime Minister Tony Blair had already promised a referendum before the UK ratifies the constitution so it can come into force.
His spokesman said: "What the foreign secretary was doing this morning was no more than setting out what are the realities of the timing.
"None of that means we have reached any definite decision on when a referendum is going to be held, not least because until parliament decides, we
The referendum would be held "irrespective" of what other countries do, he added.
Speaking on BBC Radio 4's Today programme Mr Straw said he thought if the UK held the referendum in 2006 it would not necessarily be the last vote on the issue in the EU.
"In the autumn of 2005 we have the presidency of the European Union," he continued.
"It would be practically almost impossible to combine both running the presidency with holding a referendum. That is true for any government."
Asked if a referendum would go ahead if other EU countries rejected the constitution Mr Straw said: "All sorts of things are possible."
In Rome, Mr Blair held informal talks with incoming EU commission president Jose Manuel Barroso who has withdrawn all the proposed commissioners as the result of a row about one of the candidates.
Some MEPs have objected to the appointment of Rocco Buttiglione, who recently called homosexuality a sin, as the new justice commissioner.
Mr Barroso withdrew his line-up rather than face the possibility of the European Parliament rejecting his whole team.
Tory leader Michael Howard said he did not agree with Mr Buttiglione's opinions but it would be wrong "to give in to the parliament" and allow the appointment to be overturned.
Mr Blair was one of 25 leaders to sign the EU constitution
And he argued that just as Britain had stayed out of the euro and remained in the EU, it could stay out of the constitution.
Friday's main business is the constitution signing ceremony.
The leaders put their names to the document in the same room of the Campidoglio Palace used for the signing of the Treaty of Rome in 1957, which established the European Economic Community (EEC).
The government insists it protected its "red lines" in the treaty negotiations, ensuring key issues such as defence, foreign policy, taxation and immigration will still be decided in Westminster.
But Mr Howard said the constitution would compound Europe's economic competitiveness problems.
The Tory leader added the constitution would give European judges "a pretty blank sheet of paper on which to start rewriting UK employment and trade union legislation".
Liberal Democrat foreign affairs spokesman Sir Menzies Campbell called the constitution a "sensible rationalisation" of existing EU treaties.
Green Party MEP Caroline Lucas argued the ceremony was a "dark day" for the EU which would make the institution less democratic and commit it further to a neoliberal economic agenda.
The UK Independence Party says the constitution is another step towards a European super state. It wants Britain to withdraw from the EU completely.