Induction of T cell immunity following vaccination with a recombinant vaccinia virus expressing interleukin-2 (rvv-IL-2) was studied in an orthotopic murine model (SCCVII/SF) of head and neck squamous cell carcinoma (HNSCC). Mice bearing SCCVII/SF cells in the oral cavity were vaccinated subcutaneously with irradiated, rvv-IL-2-infected tumor cells combined with intratumoral injection of rvv-IL-2, resulting in recruitment of larger numbers of CD3+ CD8+ and CD3+ CD4+ T cells in the spleen (Sp) and tumor-draining lymph nodes (TDLN) compared to control vaccine rvv-lacZ. Tumor-specific CD8+ T and CD4+ helper T cell activities in the Sp and TDLN were significantly increased in rvv-IL-2-treated mice. Sp and TDLN cells from rvv-IL-2-treated mice secreted significantly higher levels of IL-2 and IFN-gamma compared to rvv-lacZ-treated mice, while the levels of IL-4 and IL-5 were comparable. Numbers of IFN-gamma-secreting cells were also higher in rvv-IL-2-treated mice. Vaccine efficiency was completely abolished by depletion of CD8+/CD4+ T cells from rvv-IL-2-vaccinated mice. We conclude that anti-tumor activities of rvv-IL-2 are due to the induction of tumor-specific CD8+ CTL and CD4+ Th1-type helper T cells, and rvv-IL-2 may be used for treatment of HNSCC patients, since SCC VII/SF closely resembles HNSCC.