Campaigners against US drone strikes in Pakistan are calling for the CIA's former legal chief to be arrested and charged with murder for approving attacks that killed hundreds of people.

Amid growing concern around the world over the use of drones, lawyers and relatives of some of those killed are seeking an international arrest warrant for John Rizzo, until recently acting general counsel for the American intelligence agency.

Opponents of drones say the unmanned aircraft are responsible for the deaths of up to 2,500 Pakistanis in 260 attacks since 2004. US officials say the vast majority of those killed are "militants". Earlier this week 48 people were killed in two strikes on tribal regions of Pakistan. The American definition of "militant" has been disputed by relatives and campaigners.

The attempt to seek an international arrest warrant for Rizzo is being led by the British human rights lawyer Clive Stafford Smith of the campaign group Reprieve, and lawyers in Pakistan. The lawyers are also building cases against other individuals, including drone operators interviewed or photographed during organised press facilities.

A first information report, the first step in seeking a prosecution of Rizzo in Pakistan, will be formally lodged early next week at a police station in the capital, Islamabad, on behalf of relatives of two people killed in drone strikes in 2009. The report will also allege Rizzo should be charged with conspiracy to murder a large number of Pakistani citizens.

Now retired, Rizzo, 63, is being pursued after admitting in an interview with the magazine Newsweek that since 2004 he had approved one drone attack order a month on targets in Pakistan, even though the US is not at war with the country.

Rizzo, who was by his own admission "up to my eyeballs" in approving CIA use of "enhanced interrogation techniques", said in the interview that the CIA operated "a hit list". He also asked: "How many law professors have signed off on a death warrant?"

Rizzo has also admitted being present while civilian operators conducted drone strikes from their terminals at the CIA headquarters in Virginia.

Although US government lawyers have tried to argue that drone strikes are conducted on a "solid legal basis", some believe the civilians who operate the drones could be classified as "unlawful combatants".

US drone strikes were first launched on Pakistan by George Bush and have been accelerated by Barack Obama.

Much of the intelligence for the attacks is supplied either by the Pakistani military or the ISI, the country's controversial intelligence agency.

Both have blocked journalists and human rights investigators from visiting the tribal areas targeted, preventing independent verification of the numbers killed and their status.

While Stafford Smith of Reprieve estimates around 2,500 civilian deaths, others say the number is closer to 1,000. US sources deny large numbers of civilian deaths and say only a few dozen "non-combatants" have been killed.

While killing civilians in military operations is not illegal under international law unless it is proved to be deliberate, disproportionate or reckless, Stafford Smith believes the nature of the US drone campaign puts it on a different legal footing.

"The US has to follow the laws of war," he said. "The issue here is that this is not a war. There is zero chance, given the current political situation in Pakistan, that we will not get a warrant for Rizzo. The question is what happens next. We can try for extradition and the US will refuse.

"Interpol, I believe, will have to issue a warrant because there is no question that it is a legitimate complaint."

The warrant will be sought on the basis of two test cases. The first centres on an incident on 7 September 2009 when a drone strike hit a compound during Ramadan, brought by a man named Sadaullah who lost both his legs and three relatives in the attack.

The second complaint was brought by Kareem Khan over a strike on 31 December 2009 in the village of Machi Khel in North Waziristan which killed his son and brother.

Both men allege Rizzo was involved in authorising the attack. The CIA refused to comment on the allegations.

The pursuit of Rizzo will further damage US-Pakistani relations, which are already under severe strain following years of drone attacks and the killing of Osama bin Laden in May. Last week the US suspended $800m (£495m) in military aid to Pakistan.

The US launched its first drone strike against a target in Pakistan in 2004, the only one for that year. Last year there were 118 attacks after Obama expanded their use in 2009, while 2011 has so far seen 42.

The use of drones has been sharply criticised both by Pakistani officials as well as international investigators including the UN's special rapporteur Philip Alston who demanded in late 2009 that the US demonstrate that it was not simply running a programme with no accountability that is killing innocent people.