Inflammasomes are key regulators of innate immunity, and despite their known involvement in chronic inflammatory disorders and autoimmune diseases, their role in inflammation-associated tumorigenesis remains ill-defined. We discovered a pro-tumorigenic role for the key inflammasome adaptor ASC and its effector cytokine IL-18 in gastric cancer (GC). Genetic ablation of Pycard (encoding ASC) or Il18 in the gp130F/F spontaneous model of intestinal-type GC suppressed gastric tumorigenesis by augmenting caspase-8-like apoptosis in the gastric epithelium, which was independent of hematopoietic-derived myeloid cells and mucosal inflammation. Suppressed tumorigenesis in ASC-deficient gp130F/F mice was characterized by reduced caspase-1 and NF-kB activation, and lower protein expression levels of mature IL-18 (but not IL-1b) in gastric tumors. Genetic ablation of IL-18 in gp130F/F mice similarly suppressed gastric tumorigenesis, whereas blockade of IL-1b (and IL-1a) activity upon genetic ablation of the IL-1 receptor had no effect. This specific pro-tumorigenic role for IL-18 associated with high Il18 gene expression in the gastric tumor epithelium of gp130F/F mice compared to Il1b, the latter of which was preferentially expressed in immune cells. Consistent with an epithelial-specific role for IL-18 in GC, IL-18 protein was highly secreted from human GC cell lines, and reduction of IL-18 activity and protein levels either with a neutralizing anti-IL-18 antibody or upon CRISPR/Cas9-driven ASC ablation augmented human GC cell apoptosis. We also found a significant positive correlation between elevated mature IL-18 protein and ASC mRNA levels in human GC tumors. Collectively, these findings reveal the ASC/IL-18 axis as a new therapeutic target in GC.