More than 250 drone strikes have killed at least 1,500 people in north and south Waziristan since August 2008 [AFP]

The main supply route for NATO troops in Afghanistan was temporarily closed after thousands of people blocked a key highway in Pakistan to protest against US drone strikes.

The call for Sunday's blockade of the supply line came from cricketer-turn-politician Imran Khan after US officials rejected Pakistan's demand for sharp cuts in drone strikes in its tribal regions where al-Qaeda and Taliban fighters are based.

Activists from Pakistan Tehrik-e-Insaaf (PTI), Khan's party, and other parties staged a sit-in on the highway leading to Afghanistan through the Pashtun tribal region of Khyber.

A US drone attack that left at least 25 people dead in Pakistan's North Waziristan region triggered the two-day sit-in near the city of Peshawar.

Friday's attack by the unmanned drone hit a compound in Hasan Khel and was the latest in a series of such attacks to have targeted the region. 

According to the Pakistani media, the border region has been targeted by at least 20 US drone attacks this year. 

NATO resolute

According to US officials, the routes through Pakistan bring in 40 per cent of supplies for NATO forces in Afghanistan.

Of the remainder, 40 per cent comes through Afghanistan's neighbours in the north and 20 per cent by air.

The NATO-led International Security Assistance Force (ISAF) in Kabul said the two-day blockade would have no impact on the alliance's operations in Afghanistan.  

"Co-ordination with Pakistani government officials has been conducted and we understand the government will maintain security," an ISAF spokesman said. "There is no impact on ISAF sustainment."

The increasing use of drones has been mired in controversy, with remotely-controlled Predator and Reaper drones being blamed for inadvertent strikes on civilians, inflaming anti-US sentiment.