IL-1α and IL-1β (in this article referred to as IL-1) play important roles in host defense against infection and inflammatory diseases. IL-1R1 is the receptor for IL-1, and IL-1R2 is suggested to be a decoy receptor, because it lacks the signal-transducing TIR domain in the cytoplasmic part. However, the roles of IL-1R2 in health and disease remain largely unknown. In this study, we generated EGFP-knock-in Il1r2−/− mice and showed that they were highly susceptible to collagen-induced arthritis, an animal model for rheumatoid arthritis in which the expression of IL-1R2 is augmented in inflammatory joints. Il1r2 was highly expressed in neutrophils but had only low expression in other cells, including monocytes and macrophages. Ab production and T cell responses against type II collagen were normal in Il1r2−/− mice. Despite the high expression in neutrophils, no effects of Il1r2 deficiency were observed; however, we found that production of inflammatory mediators in response to IL-1 was greatly enhanced in Il1r2−/− macrophages. These results suggest that IL-1R2 is an important regulator of arthritis by acting specifically on macrophages as a decoy receptor for IL-1.