Interleukin (IL)-1 is an important mediator of inflammation and cardiovascular disease. Here, we examined the role of IL-1 in arterial neointima formation. Carotid artery neointima was induced by ligation, and arteries were harvested 4 weeks after injury. The neointima/media of mice deficient in the IL-1 signaling receptor (IL-1R1^−/−) was significantly reduced compared to IL-1R1^+/+ controls (P < 0.01). IL-1R1^+/+ mice receiving subcutaneous IL-1ra also had significantly reduced neointima/media compared with placebo (P < 0.05). IL-1β^−/− mice had reduced neointima/media compared to wild-type (P < 0.05), whereas IL-1α^−/− mice were no different from controls. Mice deficient in the P2X₇ receptor (involved in IL-1 release) or caspase-1 (involved in IL-1 activation) did not differ in their response to carotid ligation compared to controls. To examine the site of IL-1 signaling, we generated chimeric mice. IL-1R1^+/+ mice receiving IL-1R1^−/− marrow and IL-1R1^−/− mice receiving IL-1R1^+/+ marrow both had significantly reduced neointima/media compared with IL-1R1^+/+ to IL-1R1^+/+ (P < 0.05) but had significantly greater neointima/media than IL-1R1^−/− to IL-1R1^−/− controls (P < 0.05). These data confirm the importance of IL-1β signaling in mediating arterial neointima formation and suggest the involvement of IL-1 signaling in both circulating and arterial wall cells. Furthermore, receptor antagonism may be a better therapeutic target than interruption of IL-1β processing or release.