UN Ambassador Susan Rice has withdrawn her name for consideration to succeed Hillary Clinton as US secretary of state, the White House says.
In a letter to the president, Ms Rice said her confirmation process would be "disruptive and costly", NBC News said.
Ms Rice has been at the centre of Republican criticism over the Obama administration response to a deadly attack on a US consulate in Libya.
Mrs Clinton has said she will not serve a second term at the state department.
In a letter to President Barack Obama, Ms Rice said that she was "highly honoured" to be considered for the post of secretary of state and was "fully confident that I could serve our country ably and effectively in that role".
'Unfair and misleading'
But Ms Rice, 48, said the prospect of congressional opposition to her possible confirmation was behind her decision to withdraw from consideration.
Any nomination for secretary of state will need to be confirmed in the Senate by a two-thirds vote, enabling Republicans to block her potential appointment.
"I am now convinced that the confirmation process would be lengthy, disruptive and costly - to you and to our most pressing national and international priorities," Ms Rice wrote to the president.
"That trade-off is simply not worth it to our country," she added, saying "The position of Secretary of State should never be politicised."
Mr Obama said in a statement: "I deeply regret the unfair and misleading attacks on Susan Rice in recent weeks."
He added that her decision to withdraw from consideration reflected strength of character and an ability to rise above politics.
South Carolina Senator Lindsey Graham, who has spoken out repeatedly about Ms Rice' response to the attack, said he respected her decision.
"President Obama has many talented people to choose from to serve as our next secretary of state," Mr Graham added.
Correspondents say Massachusetts Senator John Kerry is now a strong candidate, with former Republican Senator Chuck Hagel reported to be a potential nominee for defence secretary.
Mr Kerry issued a statement strongly defending Ms Rice, saying: "I've defended her publicly and wouldn't hesitate to do so again because I know her character and I know her commitment.
"She's an extraordinarily capable and dedicated public servant. Today's announcement doesn't change any of that."
Ms Rice's troubles began days after the 11 September assault on the US consulate, Ms Rice said in a series of TV interviews that it seemed to have developed out of protests over an anti-Islamic film.
But later intelligence reports suggested the attack was carried out by al-Qaeda affiliates.
Her comments triggered a major political row over who knew what and when.
The attack left four Americans dead, including Ambassador Christopher Stevens.