Florida officials are investigating four cases of Zika that do not appear to be related to travel, raising fears that mosquitoes in the US are spreading the virus.
Up to now, the 1,400 infections reported in the US have been linked to people going to countries with Zika outbreaks in South America and the Caribbean.
Two new cases have been announced in neighbouring Miami-Dade and Broward counties, which raise the possibility of local Zika transmission in the US.
They are in addition to two others in the same area that may also be non-travel related.
To confirm whether Zika is being transmitted locally, experts look at households and neighbours within a 150-metre radius around the property of the Zika-infected person.
The distance of 150 metres is believed to be the flying range of the mosquitoes that carry the virus.
Health officials in Florida are investigating the possible cases, and are urging residents and visitors in the investigation areas to 'participate in requests for urine samples'.
Quoted by Reuters, CDC spokesman Tom Skinner said: "Evidence is mounting to suggest local transmission via mosquitoes is going on in South Florida.
"These cases fit similar transmission patterns for mosquito-borne diseases such as Chikungunya that we've seen in South Florida in years past," he added.
Zika transmission is defined as two or more cases which are not down to travel or sex with an infected person that occur in a one-mile diameter over a month.
Zika can lead to newborns suffering severe brain-related defects, although the disease causes only a mild illness in most people.
Health officials have predicted that mosquitoes in the US would begin spreading Zika this summer.
As a result, they increased their prevention measures to keep it from spreading beyond isolated clusters.
There have been calls to postpone next month's Rio Olympics as Brazil is one of the countries worst hit by the virus.
A drug company is embarking on America's first human trials of a vaccine.
Dr J Joseph Kim, Inovio’s President & CEO, said: "It is easy to see the potentially harmful effect Zika could have and why a safe and effective vaccine, brought to market as quickly as possible, is critical for public health."
