Background H. pylori infection causes diverse clinical outcomes, including dyspepsia, peptic ulceration, gastric carcinoma and mucosa associated lymphoid tissue (MALT) lymphoma. Up-regulation of COX-2 has been observed in H. pylori gastritis in response to inflammatory cytokines. IL-8 is a major activator for neutrophils which contribute to mucosal damage in H. pylori infected patients. A wide-spread use of non-invasive simple diagnostic method is indicated for diagnosis and follow-up of H. pylori infection. AIMS: Assessment of COX-2 and IL-8 immuno-expression in gastric mucosa in correlations to H. pylori infection in patients suffering from dyspepsia and evaluation of different available diagnostic modalities for detection of H. pylori infection in Sohag city, Egypt. METHODS: The study included 62 patients complaining of dyspepsia. Stool samples were examined for detection of H. pylori stool antigen (HpSA) using enzyme immunoassay (EIA). Antral endoscopical biopsies were taken for culture, and histopathological evaluation using Giemsa stain. Immunohistochemical expressions of IL-8 and COX-2 in tissue sections were evaluated. RESULTS: H. pylori infection was detected in 42/62 (67.7%) of patients with dyspepsia by using the gold standard method (culture & Giemsa stain). The diagnostic accuracy of HpSA was 83.8% which made it a good non-invasive alternative for detection of H. pylori infection in our community. COX-2 was expressed in 90.5% of H. pylori positive and in 55% of H. pylori negative cases (P < 0.003). IL-8 was expressed in 83.3% of H. pylori positive and in 50% of H. pylori negative cases (P < 0.003). CONCLUSIONS: Wherever endoscopy is not indicated, HpSA EIA is a non invasive, rapid, easily performed, reliable method for diagnosis of H. pylori infection. H. pylori infection causes enhancement of COX-2 and IL-8, and this may have a role in the progression of gastritis to more advanced lesions.