Three groups of specific pathogen-free (SPF) domestic cats, each containing 5 animals, were infected with one of three closely related FIV variants and monitored for 36 weeks. A fourth group of 5 cats was sham-infected and served as uninfected controls. FIV variants included: (1) a fully virulent animal passaged FIV-Petaluma; (2) a Crandell feline kidney (CrFK) cell-adapted FIV-Petaluma (FIV-CrFK); and (3) a variant of FIV-CrFK (FIV-CrFKAZT) that had been selected in vitro for resistance to azidothymidine. Cats infected with fully virulent FIV-Petaluma strongly seroconverted, became persistently viremic, and exhibited lymphadenopathy, neutropenia, and inversion of the CD4+:CD8+ T cell ratio. Cats infected with FIV-CrFK seroconverted but the antibody responses were much weaker and more variable; two of the cats became transiently viremic and no hematologic abnormalities or clinical signs of illness other than a very mild lymphadenopathy were observed. None of the five cats inoculated with FIV-CrFKAZT seroconverted, became viremic, or exhibited any gross or hematologic signs of disease, even though proviral DNA was transiently detected in tissue following inoculation. This study demonstrates that the FIV infection model can be used to assess differences in the virulence of FIV variants, including variants selected for antiretroviral drug resistance.