The United States has said Venezuela's vice president is a major drug trafficker, adding the veteran politician to its narcotics "kingpin" sanctions list.
Tareck El Aissami is seen as the likely heir to President Nicolas Maduro.
He denounced "imperialist aggression" following the claims by the US.
"TRUTH is invincible and we will see how this vile aggression will be dispelled," he said on Twitter.
The US Treasury has accused him of facilitating, protecting and overseeing large shipments of drugs from Venezuela to Mexico and the United States while serving as the country's interior minister.
His associate, Samark Lopez Bello, was also targeted for providing material assistance, financial support or goods or services in support of Mr El Aissami's activities.
In addition, the US Treasury department's Office of Foreign Assets Control also targeted 13 companies owned or controlled by Mr Lopez Bello or other parties.
The companies make up an international network spanning the British Virgin Islands, Panama, Britain, the US and Venezuela.
President Maduro frequently accuses the United States of trying to smear his administration, but US officials have denied that designations had anything to do with Mr El Aissami's prominent political role.
Since 2015, the Obama administration had sought to use behind-the-scenes diplomacy to ease hostile relations with Caracas and the fallout of a string of US drug indictments against Venezuelan officials.
Senior administration officials declined to say whether President Donald Trump had personally signed off on the sanctions or whether he was involved in the decision.
