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The Republican presidential nominee was speaking at a rally in Miami, where he contrasted his supporters, who he said back police and want crime reduced, to Clinton, who he derided as someone who "lives behind walls and raises money from hedge funds."
"I think that her bodyguards should drop all weapons. They should disarm. I think they should disarm immediately, what do you think, yes?," he said.
"Take their guns away, she doesn't want guns. Take them, let's see what happens to her. Take their guns away, okay. It will be very dangerous."
Both candidates have been protected by the Secret Service for months, but Trump's latest take on Clinton's security detail brought swift denunciations, particularly from Clinton allies.
"Tonight, Donald Trump once again alluded to violence against Hillary Clinton," said Elizabeth Shappell, spokeswoman for Correct The Record, a pro-Clinton media watchdog group.
"This is a truly deplorable comment that betrays our nation's most fundamental democratic values," Shappell said in a statement.
Stuart Stevens, a Washington-based political consultant who worked on Republican Mitt Romney's 2012 presidential campaign, tweeted: "The Secret Service should investigate this threat."
Trump made a similar comment about Clinton and her armed protection in May while accepting the endorsement of the National Rifle Association, when he said Clinton would end the U.S. Constitution's Second Amendment, which guarantees the right to bear arms.
"Let's see how they feel walking around without their guns or their bodyguards," he told the gun lobby group, speaking about Clinton and her Secret Service detail.
Trump was criticized by opponents last month when he suggested that gun rights activists could act to stop Clinton from nominating liberal U.S. Supreme Court justices, a comment some interpreted as encouraging a political assassination.
"If she gets to pick her judges, nothing you can do folks," Trump told a rally in North Carolina on Aug. 9. "Although the Second Amendment people, maybe there is, I don't know," he continued.
Clinton has called for tighter access to guns, including universal background checks, but has never said she planned to get rid of the Second Amendment.
Clinton campaign manager Robby Mook said Friday's remarks fall into a pattern of Trump inciting people to violence.
"Whether this is done to provoke protesters at a rally or casually or even as a joke, it is an unacceptable quality in anyone seeking the job of Commander in Chief," Mook said in a statement.