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All those on board the airliner - almost 300 people - are believed dead.
The plane, an Airbus A300, was making a routine flight from Bandar Abbas, in Iran, to Dubai in the United Arab Emirates.
The USS Vincennes had tracked the plane electronically and warned it to keep away. When it did not the ship fired two surface-to-air missiles, at least one of which hit the airliner.
Navy officials said the Vincennes' crew believed they were firing at an Iranian F14 jet fighter, although they had not confirmed this visually.
The plane blew up six miles from the Vincennes, the wreckage falling in Iranian territorial waters.
Iranian ships and helicopters have been searching for survivors but none have so far been found. Iranian television broadcast scenes of bodies floating amid scattered debris.
Iran has reacted with outrage, accusing the United States of a "barbaric massacre" and vowed to "avenge the blood of our martyrs".
President Reagan said the Vincennes had taken "a proper defensive action" and called the incident an "understandable accident", although he said he regretted the loss of life.
Admiral William J Crowe, Jr, chairman of the Joint Chiefs of Staff, said at a Pentagon news conference that the US government deeply regretted the incident.
However, he said, the Airbus was four miles west of the usual commercial airline route and the pilot ignored repeated radio warnings from the Vincennes to change course.
Less than an hour before the shooting down of the passenger jet, he added, the Vincennes was engaged in a gun battle with three Iranian gunboats after a helicopter from the Vincennes was fired on.
The president promised a full investigation into how a passenger jet came to be mistaken for a fighter jet, which is two-thirds smaller.
US warships have been escorting Kuwaiti tankers in and out of the Persian Gulf since last July as part of its controversial undertaking to keep the Straits of Hormuz open during the eight-year-old Iran-Iraq War.
Pentagon officials acknowledged at the time that increased US military presence would risk provoking confrontations with Iran.
Last May the patrol frigate USS Stark was almost sunk by an Iraqi fighter-bomber, killing 37 sailors. Vigilance was tightened after the incident.
Most of those on board the Iranian Airbus were Iranians on their way to Mecca. The victims also included 66 children and 38 foreign nationals.
An official inquiry carried out by the US attributed the mistake to human error.
However, the Iranian government has always disputed the American version of events.
It took four years for the US administration to admit officially that the USS Vincennes was in Iranian waters when the skirmish took place with the Iranian gunboats.
Subsequent investigations have accused the US military of waging a covert war against Iran in support of Iraq.
The US government has never admitted responsibility or apologised for the tragedy.
Some believe the Lockerbie bombing, carried out six months later in December 1988, was masterminded by Iranians in revenge for the Airbus tragedy, although a Libyan man was convicted and jailed in 2001.
In February 1996 the US agreed to pay Iran $61.8 million in compensation for the 248 Iranians killed, plus the cost of the aircraft and legal expenses.
It had already paid a further $40 million to the other countries whose nationals were killed.
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