A man who had been inside the club described a situation of chaos outside as the number of casualties became apparent.
"There were just bodies everywhere," he said. "In the parking lot, they were tagging them - red, yellow - so they knew who to help first and who not help first. Pants down, shirts cut off, they had to find the bullets. Just blood everywhere."
Footage from the scene showed dozens of emergency vehicles at the scene and people being treated on the pavements.
The injured were reportedly brought to hospital in police pick-ups as well as ambulances.
One woman said she had received a text message and phone call from her daughter inside the club, who said she had been shot in the arm.
One of the first people to tweet from the scene, local TV reporter Stewart Moore, said earlier the attacker was suspected to have had a bomb, and had taken people hostage. This has not been confirmed by the police.
Witnesses said they heard at least 20 gunshots as the incident unfolded.
More than 100 people were reported to have been enjoying a Latin-themed night in the club, which calls itself the hottest gay bar in the city, when the attack began.
Ricardo Negron Almodovar told BBC News that the shooter opened fire at around 02:00 local time (06:00 GMT), as the club night was coming to a close.
"We heard rapid fire go off. In the room I was in, people went down to the floor. I wasn't able to see the shooter or people get hurt.
"At some point, there was a brief pause, and a group of us got up and went to the exit that leads to the patio area outside. We found an exit and after that... I just ran."
Another man, Anthony Torres, said he heard people screaming that others in the nightclub were dead.
According to the Mass Shooting Tracker, there were 372 mass shootings - defined as a single incident that kills or injures four or more people - in the US in 2015. Some 475 people were killed and 1,8760 wounded.
The latest incident comes as Orlando is still reeling from the fatal shooting on Friday night of 22-year-old singer Christina Grimmie following a concert in the city.
She had been signing autographs when she was shot by 26-year-old Kevin James Loibl, who then killed himself. It is not clear what Loibl's motive was.
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