Feline immunodeficiency virus (FIV) is a lentivirus related to human immunodeficiency virus (HIV) that causes feline AIDS in the domestic cat (Felis catus). Serological surveys indicate that at least 25 other species of cat possess antibodies that cross-react with domestic cat FIV. Most infected nondomestic cat species are without major symptoms of disease. Long-term studies of FIV genome variation and pathogenesis reveal patterns consistent with coadaptation of virus and host in free-ranging FIV-Ple–infected African lions (Panthera leo) and FIV-Pco–infected pumas (Puma concolor) populations. This report examined correlates of immunodeficiency in wild and captive lions and pumas by quantifying CD5 , CD4 , and CD8 T-cell subsets. Free-ranging FIV-Ple–infected lions had immunofluorescence flow cytometry (IFC) profiles marked by a dramatic decline in CD4 subsets, a reduction of the CD4 /CD8 ratio, reduction of CD8 β ^high cells, and expansion of the CD8 β ^low subset relative to uninfected lions. An overall significant depletion in CD5 T-cells in seropositive lions was linked with a compensatory increase in total CD5− lymphocytes. The IFC profiles were altered significantly in 50% of the seropositive individuals examined. The FIV-Pco–infected pumas had a more generalized response of lymphopenia expressed as a significant decline in total lymphocytes, CD5 T-cells, and CD5− lymphocytes as well as a significant reduction in CD4 T-cells. Like lions, seropositive pumas had a significant decline in CD8 β ^high cells but differed by not having compensatory expansion of CD8 β ^low cells relative to controls. Results from FIV-infected lions and pumas parallel human and Asian monkey CD4 diminution in HIV and SIV infection, respectively, and suggest there may be unrecognized immunological consequences of FIV infection in these two species of large cats.