Tom Frieden, the chief of the US Centers for Disease Control, told reporters on a conference call that he had just returned from a visit to the US territory, and was worried about what he had seen.
"Puerto Rico is on the front lines of the battle against Zika and it is an uphill battle," said Frieden.
"I am very concerned that before the year is out there could be hundreds of thousands of Zika infections in Puerto Rico and thousands of infected pregnant women."
Some microcephaly cases have been directly linked to infection with Zika virus while the mother was pregnant.
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While researchers caution that Zika has not yet been proven to cause birth defects, evidence so far strongly suggests the possibility.
Frieden also said a link between Zika and Guillan Barre syndrome -- in which the immune system attacks the nervous system -- "is likely to be proven in the near future."
Other top concerns listed by Frieden include an apparent rise in mosquitoes' resistance to common insecticides, and the lack of access to contraception in Puerto Rico, a Caribbean island with some 3.5 million inhabitants.
"Never before have we had a mosquito borne infection that could cause birth defects on a large scale," said Frieden.
"Most of the pregnancies in Puerto Rico are unplanned, unintended and there is an unmet need for contraception."
Last month, the island territory declared a health emergency due to the Zika virus, which can be transmitted by sexual contact as well as by mosquitoes.
"There is nothing about Zika control that is quick or easy," added.
"The only thing quick is the mosquito bite that can give it to you. And the only thing easy are wrong answers.