Although feline immunodeficiency virus (FIV) and the unrelated retrovirus feline leukemia virus (FeLV) are associated with acquired immune deficiency in cats, experimental and field evidence indicates that coinfection with both viruses may lead to more serious disease syndrome. A third feline retrovirus, feline syncytium-forming virus (FeSFV), which is far more prevalent than either FIV or FeLV and is considered nonpathogenic in nature, is consistently coisolated from sick, FIV-infected cats. To determine the potential role of FeSFV in enhancement of FIV-mediated disease, persistent FeSFV infection was established in 14 of 24 nine-month-old cats. Four months later, half the FeSFV-infected and half the noninfected cats were inoculated with blood obtained from a cat persistently infected with the Petaluma strain of FIV. At postinoculation week 17, 1 male cat infected with only FIV died of bacterial bronchopneumonia that could have been attributed to FIV-induced acquired immune deficiency-like syndrome. However, none of the remaining cats had clinical illness, whether infected with either virus alone or coinfected with both viruses. As early as postinoculation week 6, decreases were observed in the CD4+ to CD8+ T-lymphocyte ratio of both groups of cats inoculated with FIV. Infection with FeSFV had no effect on the CD4, to CD8+ T-cell ratio. Mitogen stimulation assays and total WBC count were unaffected by FeSFV infection, although an increase in numbers of neutrophils from FeSFV-infected cats was consistent, especially when compared with the decrease observed after FIV infection. Overall, results of the study indicate that coinfection with FeSFV may not enhance progression of the FIV-induced early stages of disease and that the positive correlation between FeSFV and FIV-induced acquired immune deficiency-like syndrome is attributable to a common mode of transmission, rather than to a synergistic effect of coinfection.