Leukopenia attributable to lymphopenia and neutropenia was detected over a 28-week period in a 12-year-old domestic cat infected with feline immunodeficiency virus (FIV). Mild normocytic, normochronic anemia also was evident. Platelet counts were normal, and serum biochemical values were unremarkable. Antibodies to FIV were detected in serum by use of immunofluorescence and immunoblot electrophoresis assays. Cytologic evaluation of bone marrow aspirates revealed normal cellular morphologic features, maturation, and myeloid-to-erythroid ratio. Normal marrow cellularity was determined histologically. There was, however, a significant (P less than 0.01) inhibition of colony-forming unit granulocyte/macrophage-derived progenitors when marrow cells were cultured in the presence of autologous serum, compared with that when marrow cells were cultured in the presence of serum obtained from clinically normal cats, thus suggesting the presence of a humoral inhibitory substance directed specifically at the granulocyte/macrophage lineage. These cell culture results were consistent with those reported for human beings with acquired immunodeficiency syndrome and neutropenia. Thus, FIV infection may be an excellent animal model in which to study human immunodeficiency virus and should be considered in the differential diagnosis of cats with chronic leukopenia.