The resolution was overwhelmingly adopted by a vote of 191 to 2, leaving the United States and Israel as the only opposing voices in the General Assembly.
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The 193-nation assembly has voted overwhelmingly every year since 1991 to demand an end to the embargo, delivering a rebuke to Washington over its Cuba policy.
But in a first, the United States last year abstained as the administration of former president Barack Obama worked to repair relations with Havana and end more than five decades of enmity.
Taking the floor ahead of the vote, US Ambassador Nikki Haley dismissed the debate as "political theatre" and an attempt by Cuba to "distract the world's attention from the destruction it has inflicted on its own people."
"As long as the Cuban people continue to be deprived of their human rights and fundamental freedoms -- as long as the proceeds from trade with Cuba go to prop up the dictatorial regime responsible for denying those rights -- the United States does not fear isolation in this chamber or anywhere else," she said.
Haley pledged that the US decision two years ago to open diplomatic relations with Cuba would remain unchanged, saying "our friendship and good will toward the Cuban people remain as strong as ever."
The US State Department said the decision to once again vote against the UN resolution was part of a review of US policy that seeks to focus on democratic reforms in Cuba rather than building ties.
Imposed in 1959 at the height of the Cold War, the trade embargo on Cuba has remained in force and can only be lifted by the US Congress, which has steadfastly rejected such a move.
A government of millionaires
The resolution presented by Cuba stresses the "necessity of ending the economic, commercial and financial embargo imposed" by the United States against Cuba.
It noted that President Donald Trump has rolled back some of the measures taken by Obama.
Addressing the assembly, Cuban Foreign Minister Bruno Rodriguez slammed Haley's remarks as "disrespectful, offensive and interfering" and said the current US policy was a "return to the past."
"President Trump does not have the least morale authority to question Cuba," said Rodriguez.
"He is heading a government of millionaires aiming to implement savage measures against low-income families, against the poor people in this country, minorities and immigrants."
"He is pursuing a program that encourages hatred and division."
Trump in June announced new travel restrictions and banned trade with Cuban businesses linked to the military and the intelligence services, a move that put key economic sectors including tourism out of reach to American firms.
The United States restored diplomatic ties with Cuba in July 2015 and a month later re-opened its embassy in Havana. Obama made a landmark visit to the communist-ruled island in March 2016.
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