Background: Helicobacter pylori-associated gastritis is regarded as the most prevalent gastrointestinal infection, as well as the major cause of several other diseases. Despite being discovered over 30 years ago, no golden diagnostic method has yet been suggested for this microorganism. Objective: The present study aimed to compare two common diagnostic methods of histology and serology. Materials and Methods: This cross-sectional study began in July, 2016, and was conducted at Imam Jafar Sadegh Hospital (a university hospital) in Maybod, Yazd, Iran, on 70 patients. All the patients underwent endoscopy, and biopsy samples were taken for histology, as well as blood samples for ELISA test. Finally, sensitivity, specificity, NPV (negative predictive values), and PPV (positive predictive values) were calculated and analyzed. Results: The sensitivity, specificity, accuracy, PPV, and NPV of the ELISA method with histology as the gold standard were 87.5%, 36.9%, 54.2%, 42%, and 85%, respectively. Still, the histology method appears to be the most reliable test for the diagnosis of H. pylori in Iran. Conclusion: Regarding the high prevalence of H. pylori in Iran, the present study recommends the use of histology as a diagnostic method in combination with other diagnostic methods for detecting H. pylori infection.