Two Afghan officials say an altercation at the country's interior ministry has led to the deaths of two US advisers.
The two American service members killed on Saturday were inside a room only used by foreign advisers, the official said.
The interior ministry issued a statement saying that two of the ministry's international colleagues were killed, and that an investigation had been launched. Additional reports claimed the men were US military officers serving as trainers with the International Security Assistance Force in Afghanistan (ISAF).
A statement issued by NATO said "initial reports indicate an individual turned his weapon against International Security Assistance Force service members in Kabul city today, killing two service members".
In a post on his official twitter account, US Department of Defence spokesman, Captain John Kirby said there has been "lots of speculation on today's attack in Kabul. We do notT know who killed [two] ISAF members or why".
The shooting comes on the fifth day of protests across the nation sparked by the burning of Qurans at a US base.
Also on Saturday, at least four protesters were killed and 34 wounded as Afghans held protests for the fifth straight day against the burning of the Quran at a US-led base in the country, hospital officials have said.
Three of the protesters were killed at a protest outside a United Nations compound in Kunduz province on Saturday morning, hospital officials said, adding that 30 other demonstrators were wounded in that protest.
The demonstration on Saturday had initially been peaceful, but turned violent after protesters threw stones at government buildings and the UN office, said Sarwer Hussaini, a spokesman for the provincial police. He said police had fired into the air to disperse protesters.
Denise Jeanmonod, a spokeswoman for UNAMA, the United Nations' Mission in Afghanistan, confirmed the incident, saying that the organisation was "assessing the situation at the scene".
Elsewhere on Saturday, one protester was killed and four others wounded during a protest in Logar province, south of Kabul, after hundreds of angry protesters took to the streets and clashed with security forces.
Protests also erupted in several other provinces on Saturday, with demonstrations reported in Sar-e-pul and Nangarhar provinces. In Laghman province, a protest reportedly turned violent when an estimated 1,000 protesters threw rocks at police and attempted to storm the governor's house.
There were reports of casualties at that protest, but there was no immediate confirmation on the number of wounded.
On Friday, protests across the country led to the deaths of 11 Afghans, including a protester who was shot dead in the capital Kabul. It was the deadliest day of protests since demonstrations began five days ago.
Saturday's deaths bring the five-day total to 29 people killed, including two US soldiers who were shot dead on Thursday in eastern Afghanistan.
Seven protesters were killed on Friday in the western city of Herat, where protesters tried to storm the US consulate. Another protester died in the Pol-e-Khomri area of northern Baghlan province. Two deaths were also reported in the eastern province of Khost.
Hundreds of demonstrators marched toward the palace of Hamid Karzai, the Afghan president, chanting "Death to America!", prompting security forces to fire into the air in an attempt to disperse them.
Demonstrations were reported in several locations across the country, including Ghazni, Nangarhar, Paktia, Kunar, Bamiyan and Khost.
"Although peaceful demonstrations are the right of people, we strongly urge our countrymen to fully avoid turning them into violent ones," Sediqqi said earlier in the day.
Afghan political analyst Haseeb Humayoon said the rising death count in the protests showed "the room for error is reducing" for international forces in the country.
Humayoon also said "some very irresponsible actors in the political arena do actually use this for very minor, very small political ends of their own".
US President Barack Obama has sent a letter to Karzai, apologising for the unintentional burning of the Qurans at the Bagram air base. Afghan labourers found charred copies of the Muslim holy book while collecting rubbish at the base.
Two US soldiers were also killed on Thursday when an "individual wearing the Afghan army uniform" opened fire on them at a military base in Khogyani, in eastern Nangarhar province.
In a speech to soldiers at that same base, US General John Allen, commander of ISAF and US forces in Afghanistan, told the soldiers they must move beyond the deaths to continue on their mission in the central Asian nation.
"We're here for our friends. We're here for our partners. We're here for the Afghan people ... Now is how we show the Afghan people that as bad as that act was at Bagram, it was unintentional and Americans and ISAF soldiers do not stand for this" Allen said.
On Thursday, the Taliban had called on Afghans to "turn their guns on the foreign infidel invaders", but went on to say that negotiations with the US in Qatar would not be affected by the call to arms against foreign forces.
The Afghan government says that it wants those responsible for the burning to be tried publicly.
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