Frieden said officials had no immediate plans to limit travel to the area.
Further confirmation of Zika's arrival in the United States could only come by trapping a mosquito with Zika, a feat he likened to "finding a needle in a haystack."
So far no tests on mosquitoes in Florida have come back positive for the virus.
"All the evidence we have seen indicates that this is mosquito-borne transmission that occurred several weeks ago in several blocks in Miami," Frieden added.
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"We continue to recommend that everyone in areas where Aedes aegypti mosquitoes are present -- and especially pregnant women -- take steps to avoid mosquito bites."
Florida Governor Rick Scott told a news conference that one of the cases involved a woman, and the other three men. None of them needed hospitalization, he said.
- Birth defects -
Zika is spread via mosquitoes and by sexual contact. In four out of five cases, the symptoms are mild and may not be noticed at all.
But Zika poses a particular danger to pregnant women, who if infected face a higher risk of bearing an infant with microcephaly, a birth defect that causes an abnormally small head.
Florida has already seen almost 400 cases of Zika, all involving people who were infected while traveling to parts of the world where the virus is circulating.
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The United States has documented 1,657 cases of travel-related Zika in the past year, including 433 involving pregnant women, said Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases.
"This is not unexpected," said Fauci.
"I am almost certain that we are going to see more."
For Zika to become a homegrown virus in the mainland United States, a mosquito must bite a Zika-infected person and then bite another person, passing on the virus.
The virus has spread quickly throughout Central and South America and the Caribbean. The World Health Organization says 64 countries have reported mosquito-borne Zika since 2015.
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The US territory of Puerto Rico in the Caribbean has now diagnosed a total of 5,582 people, including 672 pregnant women, according to a separate CDC report out Friday.
"Puerto Rico is in the midst of a Zika epidemic," said Lyle Peterson, incident manager for the CDC's emergency response to Zika.
"This could lead to hundreds of infants being born with microcephaly or other birth defects in the coming year."
Brazil has seen the highest number of birth defects linked to Zika, with 1,749 cases of microcephaly or central nervous system malformations, according to the WHO's latest report on July 28.
- Funding fight -
Zika is not expected to spread widely in the continental United States because window screens, air conditioning and mosquito repellant are both common and effective at reducing the number of mosquitoes.
In February, the White House requested $1.9 billion to fund the Zika response but lawmakers adjourned for the summer recess earlier this month without agreeing on legislation.
President Barack Obama was briefed on the situation in Florida early Friday, a spokesman said.
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"The president has directed his team to make sure... that we're providing the resources and support to the governor that we can," said White House principal deputy press secretary Eric Schultz.
"Today's news should be a wake-up call to Congress to get back to work."
US medical groups also urged Congress to come to an agreement on Obama's request for Zika funding.
"This is the news we've been dreading," said Edward McCabe, senior vice president and chief medical officer of the March of Dimes.
"It's only a matter of time before babies are born with microcephaly, a severe brain defect, due to local transmission of Zika in the continental US."
Doctors for America executive director Alice Chen also called on Congress "to approve this emergency funding necessary to control the impending crisis, which is now a direct threat to the health of the American people."