Role of IL-18 on proliferation and survival of CD8+ T cells, activated by immobilized anti-CD3 antibody (anti-CD3), was examined. Proliferation and survival of activated T cells, especially that of CD8+ T cells, were impaired by IL-18 deficiency [IL-18 knockout (KO)]. After 3 days of culture with anti-CD3, the number of living CD8+ T cells from IL-18KO mice was approximately 25% of that from wild-type (WT) mice but was increased to the same level as WT cells by the addition of IL-18. The expression of IL-18 receptors (IL-18Rs), particularly IL-18Rbeta chain, in naïve CD8+ T cells was very low but elevated after stimulation with anti-CD3. Blockade of IL-18R by anti-IL-18R antibody on activated WT CD8+ T cells resulted in reduction of living cells, suggesting that IL-18 promotes survival of proliferating CD8+ T cells. Levels of Bcl-2 in activated IL-18KO CD8+ T cells were lower than those in WT cells but were raised by exogenous IL-18. Blockade of IL-18R on WT CD8+ T cells decreased the expression of surface markers CD122 and CD94, which are related to cell viability, and the expression of these markers was increased by exogenous IL-18 in IL-18KO cells. These results suggest that IL-18 acts directly on activated CD8+ T cells through IL-18Rs and promotes their survival to expand the population.