Primary infection with the human T-lymphotropic virus type III (HTLV-III) was documented in three patients by virus isolation during acute illness and concurrent or subsequent HTLV-III seroconversion. All patients had fevers, rigors, arthralgias, and myalgias. Additional symptoms included truncal maculopapular rash, urticaria, abdominal cramps, and diarrhea. Lymphocytic meningitis accompanied the febrile illness in two patients. The estimated incubation period was 4 to 6 weeks, and the symptoms lasted 2 to 3 weeks. Seroconversion occurred 8 to 12 weeks after presumed exposure and was manifested by a characteristic antibody response pattern. Physicians should consider the possibility of primary HTLV-III infection when evaluating patients who belong to one of the risk groups for the acquired immunodeficiency syndrome and who have prolonged febrile illnesses.