Syria must co-operate fully and unconditionally with the United Nations over the assassination in February of Rafik Hariri, Washington has said.
Assad says Syria will be accused of not co-operating whatever it does
The US state department said the UN investigator looking into the former Lebanese premier's death should get what he wanted without delay.
France and the UK made similar calls after Syria's leader said the inquiry should not harm its national interests.
Investigator Detlev Mehlis wants to question six top Syrian officials.
Among them is the brother-in-law of President Bashar al-Assad.
Mr Assad said in a televised speech on Thursday his country would co-operate with the UN inquiry because Syria was "innocent and truth is its interest".
However, co-operation would cease if Syria "would be harmed", he added, and he suggested that whatever Syria did, it would be accused of failing to co-operate.
The BBC Arab affairs analyst says President Assad's uncompromising words mean Syrian co-operation might not be as unconditional as the UN wants.
If Mr Mehlis "wants something he should get it, and he should get it without delay and without complication and without obfuscation" said US state department deputy spokesman Adam Ereli.
He was citing a UN Security Council resolution on the matter.
"It calls for Syria to make individuals requested by the commission fully available to the commission," he said.
"And it also gives the commission the authority to determine the location and modalities for the interviews."
"It's not up to Syria to negotiate terms," the US spokesman added.
Syria has until 15 December to comply with the Security Council resolution or face further action.
Syria has criticised Mr Mehlis for making accusations without due process and not offering evidence.
The killing of Mr Hariri in a car bombing in Beirut in February led to widespread criticism of Syria, which was forced to withdraw its soldiers from Lebanon as a result.