BACKGROUND AND AIMS: Proton pump inhibitors (PPIs) are used extensively in the treatment of patients with upper gastrointestinal disorders. In this study, we aimed to investigate the prevalence of PPI consumption and related factors in the Prospective Epidemiological Research Studies in Iran (PERSIAN) Guilan Cohort study (PGCS) population. METHODS: This was a cross-sectional study form the PGCS, and investigated 10,520 participants for PPI consumption, which were divided into two groups: users and nonusers. Demographical data, clinical characteristics, and PPI types were recorded. The data were analyzed using SPSS version 16 and GraphPad Prism version 9, and a significance level of 0.05 was considered. RESULTS: The prevalence of PPI use in the overall participants was 4.8%, and it was higher in females compared to males (6.1% vs. 3.3%). According to the regression analysis, being in the overweight category was associated with a 26% lower likelihood of PPI use ( CONCLUSION: This study highlights the concerning trend of increasing PPI use and identifies low physical activity, reflux, multiple underlying diseases, and NSAID use associated with higher risk of PPI use. It emphasizes the need for caution in prescribing PPIs and raising awareness among both healthcare providers and patients about the potential risks and side effects.