To clarify the role of the interleukin 1 receptor antagonist (IL-1ra) in patients with inflammatory bowel disease (IBD), we assessed the local IL-1ra concentrations in tissue homogenates using a specific enzyme-linked immunosorbent assay and examined the immunohistochemical localization using a monoclonal antibody against IL-1ra. In patients with IBD, regardless of the disease activity, the mucosal concentration of IL-1ra in affected areas was elevated, and the concentration during the active phase was comparable to that measured during the inactive phase. In contrast, the IL-1 beta tissue concentration was higher during the active than during the inactive phase. The IL-1ra/IL-1 beta tissue concentration ratio in the affected areas was decreased in patients with active IBD as compared with normal controls or patients with other types of colitis. Immunohistochemical studies identified lamina propria mononuclear cells, especially macrophages, as the major source of IL-1ra in IBD tissue. Our results suggest that IL-1ra plays a pivotal role in regulating inflammation in IBD.