Background: Proton pump inhibitors (PPI) are used for a variety of indications.Despite reported associations with undesirable effects, their long-term use is on the rise, while appropriate indications, dose, and treatment duration may deviate from guideline recommendations.Objectives: Primary to examine the annual patterns of PPI use. Secondary-to assess indications for initiating PPI treatment, long-term use, and factors associated with long-term use in a large Israeli health maintenance organization.Methods: A historical cohort study of 528 420 eligible PPI users during 2000-2015, analyzed PPI use using defined daily doses and the proportion of patients covered method. Data on indications for treatment initiation, clinical and socio-demographic parameters were captured as well. A multivariable logistic-regression model was used to identify factors associated with long-term use of PPI.Results: The annual incidence rates of patients initiating PPI treatment were relatively constant, ranging between 2.4% and 3.1% of the adult population, with a monotonic increase in annual consumption and prevalence (reaching 12.7% in 2015).Reflux, functional symptoms, and Helicobacter pylori eradication were the most common indications for initiating PPI therapy. However, 27% of patients had no recorded indication for treatment. Fifteen percent of patients used PPI for over 6 months, especially in older age groups.Conclusions: Utilization of PPI increases steadily, mainly due to chronic use. Prolonged consumption is associated with specific clinical indications and older age. Health organizations should encourage awareness of appropriate use among physicians, specifically in the elderly, patients with reflux, and those with functional disorders.