Lymphosarcoma (malignant lymphoma) is the commonest hematopoietic tumor in the cat. Many cases are associated with feline leukemia virus (FeLV) infection, but epidemiologic and experimental data suggest that feline immunodeficiency virus (FIV) may also have a role in lymphomagenesis. In this paper, we describe the clinical presentation, histologic classification, and immunophenotype of lymphosarcoma in eight domestic cats with natural or experimental FIV infections. The tumors were often of unusual distribution, with the majority of cases conforming to the least common anatomic classification of "miscellaneous." Histopathologic and immunophenotypic analysis using a panel of anti-cat and cross-reactive anti-human monoclonal and polyclonal antibodies identified seven of these tumors as high-grade B cell lymphomas of the centroblastic or immunoblastic subtypes. The remaining case was a T-cell tumor associated with a concurrent FeLV infection. Our findings, together with the results of an analysis of FIV proviral DNA in these tumors, indicate that the B-cell lymphosarcomas were comparable to those observed in human and simian immunodeficiency virus infections and that the role of FIV in lymphomagenesis is indirect and related to the potential for malignant transformation during polyclonal B cell activation.