This study was designed to examine the effects of a pre-existing, clinically asymptomatic feline immunodeficiency virus (FIV) infection on a primary challenge with Toxoplasma gondii. Parenteral challenge of FIV-infected cats with tachyzoites of the ME49 strain of T. gondii caused a precipitous drop in all lymphocytes (CD4+, CD8+, and B cells) and generalized severe toxoplasmosis. The predominant postmortem lesions included acute and often fatal interstitial pneumonia, dominated histologically by macrophages, and multifocal to coalescing hepatic necrosis. Immunohistochemistry revealed numerous T. gondii antigen and tachyzoites in macrophages and other cell types in the lung lesions. The proliferative response of peripheral blood mononuclear cells to specific (T. gondii antigen) and nonspecific (Concanavalin A) mitogens was defective in the dually infected cats, suggesting marked immunosuppression. In contrast to the dually infected cats, cats infected only with T. gondii developed a transient, mild clinical disease characterized by anorexia, lethargy, and multifocal chorioretinitis. Lymphocyte changes in T. gondii-infected cats included an early pan-lymphopenia followed by reestablishment of all lymphocyte subset profiles. These cats also showed a reduced proliferative response to Concanavalin A at 1 week after challenge, but a measurable in vivo response to T. gondii antigens, as evidenced by in vitro lymphocyte proliferation in the absence of a mitogenic stimulus. These results show that infection of cats with FIV-NCSU, markedly enhances their susceptibility to a primary T. gondii infection and provides a model to study the mechanisms of the underlying immunological defect(s) occurring early after HIV infection that may predispose individuals to development of acquired immunodeficiency syndrome and associated diseases.