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The Tree of Life Congregation Synagogue in Pittsburgh
The gunman, who opened fire as the Tree of Life synagogue held a service, was later taken into custody.
President Donald Trump said "a lot of people" had been killed and injured in a "wicked act of mass murder".
The suspect, who has been officially identified as Robert Bowers, 46, was injured and is receiving treatment.
Two other people are in hospital in a critical condition, police said.
Federal investigators are treating the shooting as a hate crime.
How did the shooting unfold?
Worshippers had gathered at the synagogue, in the Squirrel Hill neighbourhood, to mark the Sabbath.
Squirrel Hill has one of the largest Jewish populations in Pennsylvania and this would have been the synagogue's busiest day of the week.
According to reports Mr Bowers, a white male, entered the building during the Saturday morning service armed with an assault rifle and two pistols.
Reports say he barricaded himself in a room at the synagogue when police approached.
Emergency services arrived at the building at about 10:00 local time (14:00 GMT), and gunshots could be heard.
Pittsburgh's Public Safety Director Wendell Hissrich later confirmed Mr Bowers was in police custody and was being treated in hospital.
The crime scene was "horrific", he told reporters. "One of the worst I've seen, and I've [worked] on some plane crashes. It's very bad," he added.
He said that two officers were injured in an "initial confrontation" and that a further two Swat officers were later hurt by the gunman when they entered the building. He said that no children were among the casualties.
US media said he had shouted "All Jews must die" as he carried out the attack.
Social media posts by someone with the name Robert Bowers were also reported to be full of anti-Semitic comments.
Pittsburgh FBI's special agent in charge of the investigation, Bob Jones, told a press conference that he did not know if Mr Bowers was known to authorities prior to events on Saturday.
He said that any motive remains unknown but that authorities believe he was acting alone.
Mr Jones added that the investigation was "in the early stages". "We will look at every aspect of the suspect's life," he said.
Mr Bowers is receiving treatment for what has been described as multiple gunshot wounds.
•Text (excuding headline) courtesy of BBC.