We investigated the in vitro effects of combining interleukin-18 (IL-18) and IL-2 on human lymphocytes. The combined use of these two cytokines synergistically enhanced the proliferation,cytolytic activity, and interferon-γ production of peripheral blood mononuclear cells. Phenotypic analysis revealed a preferential expansion of CD56⁺CD3⁻ cells and an up-regulation of IL-2 receptor-α expression on natural killer cells. Isolated natural killer cells showed a substantial increase in proliferation and cytotoxicity compared with CD4⁺ and CD8⁺ T cells. The combined use of IL-18 and IL-2 should be considered a viable strategy to induce an antitumor response in vivo.