Hillary Clinton, the former US secretary of state, offered a tweet signed "-H" to indicate it was from her personally.
"Woke up to hear the devastating news from FL (Florida). As we wait for more information, my thoughts are with those affected by this horrific act," Clinton wrote.
Donald Trump, the presumptive Republican presidential nominee, referred to the shooting as "possible terrorism."
He was one of the first politicians to react amid reports that federal and state law enforcement officials were investigating the mass shooting as an act of terrorism.
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His reference to "possible terrorism" was a much more measured reaction than Trump issued a month ago after the EgyptAir flight crash, which he tweeted "looks like yet another terrorist attack" before authorities had addressed possible causes, CNN noted.
Meanwhile, Vermont Senator Bernie Sanders called it "horrific" and "unthinkable" and said it underscores the need for gun control measures.
"And I've got to tell you, 25 years ago, I believe that in this country, we should not be selling automatic weapons which are designed to kill people," Sanders said.
"We have got to do everything that we can on top of that to make sure that guns do not fall into the hands of people who should not have them, criminals, people who are mentally ill. So that struggles continues," Sanders, who is yet to quit the race for the Democratic Party's presidential nomination race against Hillary, said.