An able-seaman has been arrested by Hampshire Constabulary following the incident.
Southampton mayor, Carol Cunio, city council leader Royston Smith, and chief executive Alistair Neill were on board the vessel at the time of the shooting - they all escaped injury.
Police say the incident is not terrorist related and that there is no risk to public safety.
Numerous police cars, an ambulance and fire engine were all in attendance at the port's at dock gate four, as well as the Hampshire Air Ambulance, after emergency services were alerted to the
shooting by the Ministry of Defence at 12.12pm today.
The vessel arrived on Wednesday, following 46 days at sea for the 98-strong crew, for an informal five day visit.
The submarine was at 38/9 berth, with a 50 metre exclusion zone being patrolled by MoD police officers and launches at all times.
Southampton Itchen MP John Denham said: "I would like to express my deepest sympathy to the victims of this incident and their families.
"It is a matter of grave concern that an incident such as this could occur on a visiting Royal Navy vessel. In due course I will be asking Ministers to ensure this incident is fully explained with
complete openness about any potential risk to the public."
The defence secretary, Liam Fox, said: "I am greatly saddened to hear of this incident and of the death of a Royal Navy serviceman in this tragic incident.
"It is right and proper that a full police investigation is carried out and is allowed to take its course.
"My thoughts are with those affected and their families."
An MOD spokesman said: "Two Royal Navy personnel have been involved in a firearms incident at Southampton docks where HMS Astute is alongside. Sadly, one has now died as a result of his injuries.
"The Royal Navy is now attempting to inform their families as a matter of urgency. A third Royal Navy serviceman has been arrested by Hampshire Constabulary and is now in custody.
"This incident was not terrorist-related and there is no threat to the wider public. We are co-operating fully with the police investigation and a Royal Navy service investigation will begin in due
"All concerned family members should call the MOD's Joint Casualty and Compassionate Centre on 0845 7800 900."
Cllr Jeremy Moulton, deputy leader of Southampton City Council, said: “On behalf of Southampton City Council, our city and our residents, I would like to offer our sincere condolences to the
families of those Royal Navy personnel directly affected by this incident. "The visit of HMS Astute to Southampton is a matter of pride and excitement for many in the city and we are deeply
saddened by today’s events.”
• A hotline has been set up for anyone worried about relatives - 08457 800 900.
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