Zika virus, a mosquito-borne flavivirus, spread to the Region of the Americas (Americas) in mid-2015, and appears to be related to congenital microcephaly and Guillain-Barré syndrome (1,2). On February 1, 2016, the World Health Organization (WHO) declared the occurrence of microcephaly cases in association with Zika virus infection to be a Public Health Emergency of International Concern.* On December 31, 2015, Puerto Rico Department of Health (PRDH) reported the first locally acquired (index) case of Zika virus disease in a jurisdiction of the United States in a patient from southeastern Puerto Rico. During November 23, 2015-January 28, 2016, passive and enhanced surveillance for Zika virus disease identified 30 laboratory-confirmed cases. Most (93%) patients resided in eastern Puerto Rico or the San Juan metropolitan area. The most frequently reported signs and symptoms were rash (77%), myalgia (77%), arthralgia (73%), and fever (73%). Three (10%) patients were hospitalized. One case occurred in a patient hospitalized for Guillain-Barré syndrome, and one occurred in a pregnant woman. Because the most common mosquito vector of Zika virus, Aedes aegypti, is present throughout Puerto Rico, Zika virus is expected to continue to spread across the island. The public health response in Puerto Rico is being coordinated by PRDH with assistance from CDC. Clinicians in Puerto Rico should report all cases of microcephaly, Guillain-Barré syndrome, and suspected Zika virus disease to PRDH. Other adverse reproductive outcomes, including fetal demise associated with Zika virus infection, should be reported to PRDH. To avoid infection with Zika virus, residents of and visitors to Puerto Rico, particularly pregnant women, should strictly follow steps to avoid mosquito bites, including wearing pants and long-sleeved shirts, using permethrin-treated clothing and gear, using an Environmental Protection Agency (EPA)-registered insect repellent, and ensuring that windows and doors have intact screens.