Feline immunodeficiency virus (FIV) infection induces an increase in two subpopulations (CD8alpha(+)beta(low) and CD8alpha(+)beta(-)) within CD8(+) peripheral blood lymphocytes (PBLs) of cats. It is known that depletion of CD8(+) cells often results in augmentation of FIV proliferation in PBL culture, similarly to the case of human immunodeficiency virus. In this study, we attempted to define PBL subpopulations mediating antiviral activity in five cats intravaginally infected with a molecularly cloned FIV isolate. Several subpopulations (CD8alpha(+)beta(+), CD8alpha(+)beta(-), and CD4(+) cells) were shown to participate in inhibition of the FIV replication, at least in part, in a major histocompatibility complex-unrestricted manner. Moreover, the subpopulations showing anti-FIV activity were different among the individual cats.