The association between the regular use of proton pump inhibitors (PPIs) and the risk of type 2 diabetes remains unclear, although a recent randomised controlled trial showed a trend towards increased risk. This study was undertaken to evaluate the regular use of PPIs and risk of type 2 diabetes.This is a prospective analysis of 204 689 participants free of diabetes in the Nurses' Health Study (NHS), NHS II and Health Professionals Follow-up Study (HPFS). Type 2 diabetes was confirmed using American Diabetes Association (ADA) diagnostic criteria. We evaluated hazard ratios (HRs) adjusting for demographic factors, lifestyle habits, the presence of comorbidities, use of other medications and clinical indications.We documented 10 105 incident cases of diabetes over 2 127 471 person-years of follow-up. Regular PPI users had a 24% higher risk of diabetes than non-users (HR 1.24, 95% CI 1.17 to 1.31). The risk of diabetes increased with duration of PPI use. Fully adjusted HRs were 1.05 (95% CI 0.93 to 1.19) for participants who used PPIs for >0-2 years and 1.26 (95% CI 1.18 to 1.35) for participants who used PPIs for >2 years compared with non-users.Regular use of PPIs was associated with a higher risk of type 2 diabetes and the risk increased with longer duration of use. Physicians should therefore exercise caution when prescribing PPIs, particularly for long-term use.