The proinflammatory cytokine interleukin (IL)‐1β is up‐regulated in microglial cells surrounding amyloid plaques, leading to the hypothesis that IL‐1β is a risk factor for Alzheimer’s disease. However, we unexpectedly found that IL‐1β significantly enhanced α‐cleavage, indicated by increases in sAPPα and C83, but reduced β‐cleavage, indicated by decreases in sAPPβ and Aβ40/42, in human neuroblastoma SK‐N‐SH cells. IL‐1β did not significantly alter the mRNA levels of BACE1, ADAM‐9, and ADAM‐10, but up‐regulated that of TACE by threefold. The proform and mature form of TACE protein were also significantly up‐regulated. A TACE inhibitor (TAPI‐2) concomitantly reversed the IL‐1β‐dependent increase in sAPPα and decrease in sAPPβ, suggesting that APP consumption in the α‐cleavage pathway reduced its consumption in the β‐cleavage pathway. IL‐1Ra, a physiological antagonist for the IL‐1 receptor, reversed the effects of IL‐1β, suggesting that the IL‐1β‐dependent up‐regulation of α‐cleavage is mediated by the IL‐1 receptor. IL‐1β also induced this concomitant increase in α‐cleavage and decrease in β‐cleavage in mouse primary cultured neurons. Taken together we conclude that IL‐1β is an anti‐amyloidogenic factor, and that enhancement of its signaling or inhibition of IL‐1Ra activity could represent potential therapeutic strategies against Alzheimer’s disease.