Another American soldier was missing after the blast, which caused one of the deadliest days for U.S. forces since they deployed here two years ago. An Afghan interpreter also was wounded.
The explosion occurred Thursday afternoon as the soldiers worked around the cache in the village of Dehe Hendu, about 140 kilometers (90 miles) southwest of the capital, Kabul, in Ghazni province.
Lt. Col. Bryan Hilferty, a spokesman at U.S. military headquarters in Kabul, said investigators were trying to determine if the blast was accidental or an attack.
He said there were no indications of "active enemy activity" at the site of the explosion. But Hilferty added: "It could have been a booby-trap. That is one of the things that we are investigating."
Hilferty said it was unclear whether the soldiers were handling the weapons, which he said included rifle ammunition and mortar rounds. He gave no details of where the weapons were concealed.
But Ghazni province Gov. Haji Asadullah Khan said the blast was set off by mistake as the U.S. soldiers were trying to defuse arms at an old weapons depot found in an open area.
"I'm sure it wasn't a plot by the Taliban," Khan said. "We know the area and the people are good."
Coalition soldiers regularly uncover and destroy caches of weapons, much of it dating back to the U.S.-backed mujahedeen resistance against the Soviet occupation in the 1980s. Residents often lead military units to the caches — a sign, the military says, that it is winning the confidence of Afghans tired after almost a quarter-century of strife.
The wounded soldiers from Thursday's explosion were evacuated to a hospital at Bagram Air Base, the main camp of the U.S.-led coalition in Afghanistan. Hilferty said the three soldiers and the interpreter were released after treatment.
Names of the victims were being withheld pending notification of relatives.
The deaths come at the end of a bloody month that has underlined the danger and instability still plaguing Afghanistan two years after a U.S.-led invasion ousted the hard-line Islamic Taliban regime for harboring Osama bin Laden and the al Qaeda network.
This month alone, about 80 people have died in violent incidents in Afghanistan, including civilians, militants, police officers, international peacekeepers and now American soldiers.
Only sixteen U.S. soldiers died in the initial combat in Afghanistan in 2001, but the death toll earlier this month from all anti-terrorist missions worldwide under Operation Enduring Freedom reached 100 — of those about two-thirds in Afghanistan, half in combat and the rest in accidents.
The United States provides 9,000 of the 11,000-member anti-terror coalition troops stationed in Afghanistan. Officials say U.S. forces are preparing a spring offensive against Taliban and al Qaeda holdouts amid concern that operations in Afghanistan haven't been as effective in breaking up terrorist networks as they had hoped.
Separately, investigators are also sifting through evidence from suicide bombings that killed British and Canadian soldiers in Kabul earlier this week. The Taliban has claimed responsibility for both blasts, alleging they are the start of a bombing campaign across the country.
British troops held a memorial ceremony Thursday for Pvt. Jonathan Kitulagoda, 23, of Plymouth in southwest England, killed the day before by a suicide bomber.
Commanders and diplomats joined about 150 soldiers to hear readings, prayers and tributes from Kitulagoda's friends in a private gathering, said Capt. Tom Smith, spokesman for the 300-strong British contingent. Kitulagoda's body likely will be flown home next week, he said.
Kitulagoda was killed when a suicide bomber detonated a yellow-and-white taxi next to an unarmored jeep. Four other British soldiers were wounded. That attack came a day after a Canadian soldier was killed in a similar suicide attack.