We demonstrated earlier that post-exposure prophylaxis with 3'-azido-3'-deoxythymidine (AZT, zidovudine) or with AZT + interferon-alpha (IFN-alpha) prevented viremia and disease in BALB/c mice inoculated with Rauscher murine leukemia virus (RLV). After the 20-day treatment course, most animals were resistant to rechallenge with live virus. Adoptive transfer of T cells from such resistant but not from normal mice into naive recipients provided full protection against virus challenge. From these experiments, we concluded that post-exposure chemoprophylaxis restricted virus replication and allowed the animals to form protective, long-lasting cellular immune responses. Here, the role for cellular immunity during antiviral chemoprophylaxis was tested by comparing treatment success in normal BALB/c mice and in their nude, athymic counterparts. Both were inoculated with equal doses of RLV (10(4) plaque-forming units, pfu). Single-agent AZT or combination therapy with AZT + IFN-alpha, started before or after RLV inoculation, prevented viremia in all normal but not in most nude mice. A significant number of nude mice were completely protected by chemoprevention only when given a 10 times lower virus dose. When normal mice were injected with a 10 times higher virus dose (10(5) pfu), complete protection by chemoprevention was lost. These results demonstrate that the success of chemoprevention depends critically on the virus inoculum. The differential success of chemoprevention in normal and T-cell-deficient mice implies that effective cellular immunity plays an important role in protecting virus-exposed animals against viremia and disease.