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Four members from the USS Minneapolis went overboard as the submarine left Devonport, Plymouth, Devon.
A rescue helicopter was called in from RNAS Culdrose along with the Plymouth lifeboat and a tug.
All four were brought in and taken to Derriford Hospital, Plymouth where two were pronounced dead. The other two have since been released.
The identities of the deceased crew are not being released until their next next of kin have been informed.
A United States military spokesman said: “Four sailors from the USS Minneapolis fell overboard today when getting under way from Devonport.
“All four were rescued and taken to hospital where two were pronounced dead.
The other two were checked and have been released.
“The names of the sailors are being withheld until their next of kin have been informed.
“The submarine had just completed a week long visit to Plymouth.”
The two men who were released from hospital have now been transferred to HMS Drake at the Royal Navy base in Plymouth.
The American nuclear-powered attack submarine is based in Norfolk, Virginia, and has since continued on its journey.
An American spokesman said an investigation was under way, but did not say what the four were doing on the outside of the submarine.
“We don’t know the details of what they were doing,” he said. “The submarine was in the process of leaving port, what happened will be clear after the investigation.”
A Devon and Cornwall Police spokesman confirmed that two of the crew were pronounced dead this afternoon and the coroner was being informed.
The spokesman said: “It was immediately apparent that two of the servicemen were in distress and CPR was commenced as they approached the shore where they were met by ambulance personnel.
“It has now been confirmed that two of the sailors have died. The other two sailors were transferred to the sick bay at the shore establishment HMS Drake.
“An investigation by the Devon and Cornwall Constabulary, working with the Ministry of Defence police and the military has commenced.”
The submarine has a complement of 137 enlisted officers and crew and can reach speeds exceeding 25 knots.
Its weapons include torpedoes and Tomahawk cruise missiles.
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