Several persons were also injured when drones fired at least four missiles at the compound in Buland Khel area of Orakzai Agency, officials were quoted as saying by TV news channels.
Several foreigners were among the dead, the officials said.
A madrassa was being run in the compound by Maulvi Shakirullah, who has links with a Taliban faction led by Hafiz Gul Bahadur, officials and local residents said.
The compound is located in an area close to North and South Waziristan tribal regions.
Shakirullah's group is also believed to have links with the Haqqani network and al-Qaeda.
The CIA-operated spy planes have rarely carried out attacks in Orakzai region since the US launched its drone campaign in Pakistan's tribal belt.
This was only the second drone attack in Orakzai Agency and the first was carried out in 2009.
Today's attack was also the second missile strike since Pakistan Tehrik-e-Insaf chief Imran Khan led a large rally against US drones over the weekend.
Khan, a leading opponent of the drone campaign, was barred from entering South Waziristan Agency by the army for security reasons.
US officials say parts of the tribal belt are a safe haven for Taliban and Al Qaeda elements, including the Haqqani network that has carried some of the deadliest attacks in Afghanistan.
The Pakistan government says the drone strikes violate its sovereignty and are counter-productive.
