Previous studies have demonstrated elevated serum levels of interleukin-6 (IL-6) and the soluble interleukin-2 receptor (IL-2R, CD25) in individuals with inflammatory bowel disease (IBD). The aim of our study was to compare serum IL-6 and IL-2R levels to see if one marker better distinguished IBD from other intestinal disorders or better reflected disease activity. Blood samples were obtained from 41 pediatric patients with Crohn's disease, 22 with ulcerative colitis, 19 with other gastrointestinal inflammatory disorders, and 13 with functional abdominal pain. Disease activity and disease location were determined for patients with Crohn's disease and ulcerative colitis. Serum levels of IL-6 and IL-2R were determined by using an enzyme-linked immunosorbent assay. Mean serum levels of IL-6 were significantly elevated (p < 0.05) in patients with Crohn's disease when compared with individuals with ulcerative colitis, other gastrointestinal inflammatory disorders, or functional abdominal pain. By comparison, there was no significant difference in mean serum levels of IL-2R in individuals with Crohn's disease compared with these other groups. Patients with moderate/severe Crohn's disease had elevated mean serum levels of IL-6 and IL-2R when compared with those with mild and inactive disease (p < 0.05); however, neither marker distinguished between inactive and mild disease. IL-6 correlated better with the erythrocyte sedimentation rate (ESR; r = 0.57, p < 0.001) than did IL-2R (r = 0.28, p < 0.01). Our results suggest that elevated IL-6 levels a.e more likely to be seen in patients with Crohn's disease. Although IL-6 may be a better marker for Crohn's disease and active disease than IL-2R, it does not appear to offer any advantage over the ESR.