The cytokines IL-1 beta and IL-6 appear to be important in the pathogenesis of inflammatory bowel disease (IBD). Recently, a naturally occurring interleukin-1 receptor antagonist, designated IL-1ra, which inhibits IL-1 beta activity in vitro and in vivo has been described. The purpose of the present study was to assess the circulating levels and relative relationships of IL-1ra, IL-1 beta, and IL-6 in children with IBD of varying severity. Serum/plasma samples were obtained from 32 children with ulcerative colitis, 45 with Crohn's disease, and 24 control patients. Cytokine assays were performed by enzyme-linked immunoassay. IL-1ra levels were significantly elevated in children with ulcerative colitis or Crohn's disease of moderate/severe activity compared to patients with inactive/mild IBD or control subjects (P < 0.001). IL-1 beta was only detectable in the circulation of two subjects with severe colitis (one ulcerative colitis, one Crohn's disease), and both had extremely elevated IL-1ra levels. IL-1ra levels were significantly related to IL-6 levels for patients with IBD (P < 0.00001). Our results suggest that circulating IL-1ra appears in increasing concentrations in children with mounting degrees of disease severity as determined by clinical scoring methods as well as by the level of IL-6. Future work will need to address the clinical and prognostic value of measuring circulating IL-1ra in individuals with inflammatory bowel disease.