: This study aims to present the usability of real-time polymerase chain reaction (PCR) and interferon-gammarelease assay (IGRA) in the differential diagnosis of granulomatous appendicitis (GAp), especially in areas where tuberculosis (TB) is endemic. METHODS: Sixteen patients underwent appendectomy with presumed diagnosis of acute appendicitis were retrospectively analyzed for histopathological diagnosis of GAp. Real-time PCR method was used to show the whether presence of DNA of the tubercle bacilli in paraffin-embedded tissue blocks. IGRA test was used to investigate whether tubercle bacilli- specific interferon gamma was present in peripheral blood. RESULTS: Sixteen patients (male: 10 female: 6) aged between 21 and 82 years were included in this study. All patients had acute appendicitis and three of them also had appendiceal perforation. Histopathologically, necrotizing granulomatous inflammation was detected in all appendectomy specimens. Acid-fast bacilli were not detected in any of the pathology slides stained with Ehrlich-Ziehl-Neelsen . Real-time PCR was studied in paraffin-embedded tissue blocks of all patients with GAp, but the TB bacilli DNA was amplified in only three patients. IGRA test was studied in peripheral blood samples of 12 patients with GAp and results were as follows: negative (n=9), positive (n=2) and indeterminate (n=1). CONCLUSION: We believe that the use of anamnesis, histopathological findings, tissue PCR, blood IGRA and clinical findings together are important for differential diagnosis of GAp, especially where TB is endemic. We also suggest that all appendectomy specimens should be sent to the laboratory for histopathological evaluation even if specimens appear macroscopically normal. Keywords: Acute appendictis; granulomatous appendicitis; interferon-gamma release assay; perforated appendicitis; polymerase chain reaction.