Fifty people are now known to have died in a shooting in a gay nightclub in Orlando, Florida, the city's mayor Buddy Dyer has said.
The gunman, named by officials as Omar Mateen, was killed after taking hostages at the Pulse club.
President Barack Obama said Americans were united in grief, outrage and "resolve to defend our people" after "an act of terror and an act of hate".
The attack is the worst mass shooting in recent US history.
A nationwide moment of silence will be held at 18:00 local time (22:00 GMT).
Officials said the killings were likely to be ideologically motivated, though there was no information that the gunman was associated with a particular group.
However, US Congressman Alan Grayson said it was "no coincidence" the attack happened in a gay club.
"It may be we've seen the commission of an awful hate crime," he added.
Mateen's father Mir Seddique told NBC News that the incident had nothing to do with religion, and may have been triggered by the sight of a gay couple kissing in Miami.
But NBC News reported that Mateen called the emergency services before the attack and swore allegiance to the so-called Islamic State (IS) militant group.
The group later said - via its affiliated Amaq news agency - that an IS "fighter" had carried out the attack.
The claim did not specify whether IS was directly involved or simply taking credit for inspiring the attack.
Mr Obama described the attack as "the brutal murder of dozens of innocent people".
"It was an act of terror and an act of hate," he said, adding that it was a heartbreaking day for the LGBT community.
An attack on any American was an attack on all, he added. "We are united in grief, in outrage and resolve to defend our people."
Mr Obama has ordered flags on federal buildings to be flown at half mast until sunset on Thursday.
French President Francois Hollande expressed "horror" at the killings, and said Americans had the "full support of France" in this "difficult time".
Pope Francis condemned the "homicidal folly" of the shooting.
The suspect, who was a US citizen from the Florida town of Port St Lucie and was of Afghan descent, was not on a terrorism watch list.
However, officials revealed that the FBI had twice interviewed Omar Mateen in 2013-14 after he made "inflammatory remarks" to a colleague. But the investigation was closed.
The death toll of 50 given by Mayor Dyer means that the Orlando attack surpasses the 2007 massacre at Virginia Tech which left 32 people dead.
Another 53 people were injured in the shooting.
"Today we're dealing with something that we never imagined and is unimaginable," he said, adding that there was "an enormous amount of havoc" and "blood everywhere".
"Because of the scale of the crime I've asked the [Florida] governor to declare a state of emergency," he said.
"We're also issuing a state of emergency for the city of Orlando so that we can bring additional resources to bear to deal with the aftermath."
Security has also been boosted for the last day of the Capital Pride LGBT festival in Washington DC, which included a moment of silence for the Orlando victims at 13:00 local time, the Washington Post reported.
A gay pride parade has also been taking place in West Hollywood, Los Angeles. The city's mayor said police in the nearby city of Santa Monica had arrested a heavily armed man who said he was going to the parade.
Worst US mass shootings in last 25 years
- At least 50 dead, 2016 - Omar Mateen opens fire on revellers at gay club in Orlando, Florida
- 32 dead, 2007 - Student Seung-Hui Cho massacres students at Virginia Tech university before killing himself
- 27 dead, 2012 - Adam Lanza kills 20 six- and seven-year-old children and six adults before killing himself at Sandy Hook, Connecticut
- 23 dead, 1991 - George Hennard drives through the wall of a cafe in Killeen, Texas, before opening fire and committing suicide
- 14 dead, 2015 - Syed Rizwan Farook and Tashfeen Malik open fire at a staff gathering in San Bernardino
- 13 dead, 2009 - Maj Nidal Malik Hasan opens fire at army base in Fort Hood, Texas
- 13 dead, 2009 - Jiverly Wong shoots people at New York immigrant centre before killing himself
- 13 dead, 1999 - Eric Harris and Dylan Klebold kill fellow students and a teacher at Columbine High School in Littleton, Colorado
Orlando Police Chief John Mina said the attack began at 02:00 (06:00 GMT). There was an exchange of fire with a police officer working at the club, but it is unclear whether that was inside or outside the venue.
After this a "hostage situation" unfolded, he said.
Chief Mina said a decision was taken at 05:00 to send a police assault team into the club after receiving texts and phone calls from some of the hostages.
He said the suspect, who appeared to be carrying an assault-type rifle and a handgun, was shot dead in an exchange of fire with 11 officers.
It has also emerged that the suspect legally purchased multiple guns in the past few days.
According to the Mass Shooting Tracker, the US last year suffered 372 mass shootings, defined as a single incident that kills or injures four or more people. Some 475 people were killed and 1,870 wounded.
The latest incident came as Orlando was still reeling from the fatal shooting on Friday night of 22-year-old singer Christina Grimmie following a concert in the city.
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