BACKGROUND: Appendicitis is a very common surgical diagnosis with unclear pathology. Human cytomegalovirus (HCMV) can modulate our immune system and has been associated with inflammatory bowel disease (IBD) and various other inflammatory diseases. METHODS: We investigated the association between HCMV and acute appendicitis in 14 immunocompetent patients. Tissue sections from 10 AIDS patients with verified HCMV infection were used as positive controls, and uninflamed intestinal tissue sections from 12 patients were used as negative controls. RESULTS: Cells double positive for HCMV early antigens and IL-6/IL-8 were observed in the appendices of 64.3% of appendicitis patients (9 of 14) by immunohistochemical analysis. HCMV late antigen was found in the appendices of 42.9% of the acute appendicitis patients (6 of 14). Latent HCMV appendix infection, as verified by in situ hybridization, as well as HCMV IgG, was observed in 78.6% of patients (11 of 14). The study samples from all 6 healthy appendices were negative for HCMV early and late antigens, although 50% (3 of 6) were HCMV IgG and HCMV DNA positive. CONCLUSIONS: We have shown that HCMV infection of the appendix is associated with acute appendicitis (P = 0.002) and possibly with the severity of the disease. Our study identified HCMV as a pathogen to be sought for in the appendicitis patient group, possibly allowing further medical treatment of these patients.