Two officials say Wednesday's attack occurred near Miran Shah, the main town in the North Waziristan tribal region.
It's the first drone strike since an American missile fired June 4 killed al-Qaida's second-in-command, Abu Yahya al-Libi.
The identity and nationality of the men killed Wednesday is not immediately known and the officials say their agents are trying to get more details.
Washington has pushed on with its drone campaign against suspected Taliban and al-Qaida operatives in Pakistani tribal areas, despite Pakistani objections.
The officials spoke on condition of anonymity because they were not authorized to speak to the media.