Appendicitis is a common surgical problem that is associated with a systemic inflammatory response. Previous studies have shown that cytokines are activated early in acute inflammation and sepsis and may serve as indicators of clinical severity. In this study we examined the role of cytokines as serum markers to distinguish nonperforated versus perforated appendicitis. Patients with the presumptive diagnosis of appendicitis had serum drawn preoperatively. Only patients (n = 59) with an intraoperative diagnosis of nonperforated (n = 34) and perforated (n = 25) appendicitis had serum drawn 12 hours postoperatively. Diagnosis was later confirmed by pathologic examination. The serum specimens were batch analyzed using enzyme-linked immunosorbent assays specific for interleukin (IL)-1beta, IL-2, IL-6, IL-8, and IL-10. Serum from normal healthy subjects served as control specimens (n = 9). Patients in the nonperforated and perforated groups were similar with regard to age, gender, race, white blood cell count, and fever. All cytokine levels including preoperative, postoperative, nonperforated, and perforated were higher in patients with appendicitis as compared with controls. IL-1beta, IL-2, and IL-10 levels were not different between groups with appendicitis. Preoperative serum levels of IL-6 (P = 0.036) and IL-8 (P = 0.047) were higher in patients with perforated versus nonperforated appendicitis. In addition postoperative serum levels of IL-6 (P = 0.0001) remained higher in the perforated group versus the nonperforated group. Serum levels of IL-6 and IL-8 may have a role in discerning the extent of disease in this condition. This initial step in systemically studying the role of cytokines in this disease may ultimately lead to the development of molecular indicators to aid in diagnosis and differentiate appendicitis from other conditions.