The aim of this study was to examine the effects of the antiviral drug amantadine (AMN) administered in combination with thymosin alpha 1 (T alpha 1) and murine alpha/beta interferon (IFN) on mice infected with influenza A PR8 virus. Combined treatment with AMN and T alpha 1, for 4 days, followed by a single injection of IFN, was initiated 1 h after intranasal viral inoculation. The effectiveness of this new chemoimmunotherapy protocol was seen in the long-term survival of a high percentage of animals and was statistically significant when compared to treatment with single agents in conjunction with chemotherapy or to chemotherapy alone. In addition, chemoimmunotherapy treatment reduces the viral titre in the lungs as well as restoring the immunological parameters tested (natural killer cell activity; cytotoxic T-lymphocyte responses; CD4+/CD8+ lymphocyte subsets) with respect to all other groups. These results suggest the potential use of these immunomodulating agents in combination with an antiviral drug in controlling PR8 influenza virus infection.