Feline leukemia virus (FeLV) infection of cats is a model for the acquired immunodeficiency syndrome in humans. The toxicity of zidovudine was evaluated in SPF cats experimentally infected with FeLV. At initiation of the zidovudine study, all cats were antibody positive for FeLV antigens but clinically asymptomatic. Four cats were also viremic. Thirteen, 6- to 10-month-old cats were divided into five dosage groups and given zidovudine po at 0, 7.5, 15, 30, or 60 mg/kg daily in three equally divided doses for 32 to 34 days. Titers of circulating virus antigen remained constant; however, three of six cats receiving the higher doses of zidovudine (greater than or equal to 30 mg/kg) showed an increase in antibody titers to FeLV. Administration of zidovudine resulted in a progressive anemia, dependent upon dose and time. Macrocytes were observed prior to the development of anemia and were also found in several nonanemic cats. Repeated measures regression analyses indicated that an increased dose of zidovudine was associated with decreased packed cell volume, red blood cell count, and hemoglobin. As determined from the packed cell volume, the analyses indicate that anemia is induced only by the two highest doses of zidovudine. The regression model indicates that daily doses of 60 and 30 mg/kg are expected to induce anemia by Day 4 and Day 13, respectively. Progressive absolute neutropenia was observed in the greater than or equal to 30 mg/kg groups. Histopathologic lesions consisted of marked bone marrow hypercellularity in cats given greater than or equal to 30 mg/kg zidovudine and splenic extramedullary hematopoiesis in cats given greater than or equal to 15 mg/kg. Thus, oral toxicity of zidovudine in the cat is manifested by a dose-related anemia and neutropenia as observed in humans.