Polymorphisms of interleukin-1β (IL-1β) are associated with an increased risk of solid malignancies. Here, we show that stomach-specific expression of human IL-1β in transgenic mice leads to spontaneous gastric inflammation and cancer that correlate with early recruitment of myeloid-derived suppressor cells (MDSCs) to the stomach. IL-1β activates MDSCs in vitro and in vivo through an IL-1RI/NF-κB pathway. IL-1β transgenic mice deficient in T and B lymphocytes develop gastric dysplasia accompanied by a marked increase in MDSCs in the stomach. Antagonism of IL-1 receptor signaling inhibits the development of gastric preneoplasia and suppresses MDSC mobilization. These results demonstrate that pathologic elevation of a single proinflammatory cytokine may be sufficient to induce neoplasia and provide a direct link between IL-1β, MDSCs, and carcinogenesis.