The ability of cytokines to steer CD4⁺ T_h cell responses toward a T_h1 or T_h2 phenotype and enhance the magnitude of both CD8⁺ cytotoxic T lymphocytes (CTL) and antibody responses has clearly been demonstrated by our lab and others, but the influence of cytokines on protective immune responses is much less clear. Here we show an essential role for CD4⁺ T_h1 helper cell induction and IFN-γ production in protection from viral challenge with a recombinant vaccinia virus expressing HIV-1MN viral envelope glycoprotein gp160. Complete protection from viral challenge is achieved only when the triple combination of exogenous cytokines granulocyte macrophage colony stimulating factor (GM-CSF), IL-12 and tumor necrosis factor (TNF)-α are co-administered with the peptide vaccine. In vivo depletion of CD4⁺ cells or immunization of IFN-γ-deficient mice abrogates protection. GM-CSF, IL-12 and TNF-α also synergize for the enhanced induction of CTL; however, adoptive transfer of a CD8⁺ CTL line afforded only partial protection in this viral challenge model. As a possible mechanism of in vivo protection we show that GM-CSF increases the percentage and activity of antigen-presenting dendritic cells in draining lymph nodes where the immune response is initiated. We further demonstrate synergy between IL-12 and the proinflammatory cytokine TNF-α in driving IFN-γ production. Thus, a combination of IL-12 and TNF-α is essential for the optimal development of T_h1 responses and help for CTL induction in BALB/c mice, and is complemented by a third cytokine, GM-CSF, which enhances antigen presentation.