"We believe that the UK government's decision to hold a referendum on EU membership by 2017 indicates that economic policymaking could be at risk of being more exposed to party politics than we had previously anticipated," the credit ratings agency said in a statement.
It recalled it had lowered the US's sovereign rating in 2011, when sharp political disagreements between Democrats and Republicans nearly pushed the country into default.
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The referendum was a campaign promise in last month's election. The prime minister backs Britain's continuing membership in the EU, but dozens of MPs look set to support leaving.
Comments by Cameron this week triggered a row about whether ministers in his government would have to resign if they did not campaign for Britain to remain in Europe.
"A possible UK departure from the EU also raises questions about the financing of the economy's large twin deficits and high short-term external debt," said Standard and Poor's.
"We are therefore revising the outlook to negative from stable and affirming the 'AAA/A-1+' ratings on the UK," it added.
Despite austerity measures that Cameron introduced during his first term in office at the head of a Conservative-Liberal Democrat coalition government, Britain has yet to bring its budget back into balance and begin to cut its debt.
The deficit remains stubbornly high, at 5.2% of GDP in the 2014-2015 fiscal year, well above the EU limit of 3% and debt stands at almost 90% of gross domestic product (GDP), according to the Maastricht criteria, comparable with other EU countries.
Standard and Poor's put it at 83% of GDP this year, which it noted is slightly higher than that of the US at 80% and is the most elevated among all AAA rated sovereigns.
The ratings agency said the Conservative government might also have a difficult time trying to negotiate a better deal with the EU while also working on a constitutional settlement to devolve wide-ranging powers to Scotland.
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