Aim: Proton-pump inhibitors (PPI) are extensively prescribed worldwide. However, little information is available on PPI prescribing patterns, associated clinical and demographic factors, and potential drug-drug interactions in frail older patients. Methods: Data on clinical and demographic characteristics, and full medication exposure were collected in a consecutive series of 361 older patients (age 84±7years) admitted to two acute geriatric admission units (Aberdeen, National Health Service Grampian) between 1 February 2010 and 30 June 2010. A set of predetermined criteria was used to assess appropriateness of PPI prescribing. Results: PPI were prescribed in 148 patients (41.0%). Inappropriate overprescribing was observed in 127 patients (35.2% of the study population, 85.8% of patients prescribed PPI). PPI were inappropriately not prescribed in 20 patients (48.8% of patients with an indication for PPI treatment). Regression analysis showed that the total number of non-PPI prescribed drugs (OR 1.08; 95%CI 1.01-1.15) and a higher Charlson Comorbidity Index (OR 1.08; 95%CI 1.001-1.16) were independently associated with inappropriate PPI overprescribing. Potential drug-drug interactions were found in 75 patients (22.8% of the study population), mainly in patients with PPI overprescribing. Conclusions: Inappropriate PPI prescribing is common in frail older hospitalized patients, and might increase the risk of drug-drug interactions. Polypharmacy and comorbidity were independently associated with inappropriate PPI prescribing in this group. Geriatr Gerontol Int 2013; 13: 1002-1009.