Background: The prevalence of Helicobacter pylori (H. pylori) infection is reported to be more than 50% worldwide. It has been associated with peptic ulcer disease, gastric carcinoma, and mucosal-associated lymphoid tissue lymphoma. The seroprevalence of H. pylori varies greatly among societies and geographical locations. The objective of this study was to determine the seroprevalence and factors associated with H. pylori infection among dyspeptic patients in Afghanistan. Materials and Methods: This cross-sectional study was designed to determine the seroprevalence of H. pylori among dyspeptic patients in an outpatient clinic in Andkhoy, Afghanistan from January 2017 to April 2017. Data were obtained from patients using a questionnaire, including socio-demographic data and history of smoking and dyspeptic symptoms. Serum samples were also collected from the patients and tested for H. pylori antibodies using the enzyme-linked immunosorbent assay. Results: A total of 152 patients with dyspepsia were included in the analysis; 59 were men (40.0%), and 93 were women (60.0%). The overall seroprevalence of H. pylori was 75.6%. The predictor of seroprevalence of H. pylori was found to be illiteracy (odds ratio [OR] 4.99, 95% confidence interval [CI] 1.03¬24.17), epigastric pain (OR 12.01, 95% CI 3.56- 40.52), and rural population (OR 9.66, 95% CI 3.36- 27.82). There was an inverse association between employed status and seroprevalence of H. pylori (OR 0.08, 95% CI 0.01- 0.52). Conclusions: The seroprevalence of H. pylori was high among patient with dyspepsia in an outpatient clinic in Afghanistan. Illiteracy, unemployment and rural populations, and epigastric pain were significantly associated with H. pylori infection.