Background The potentially inappropriate medications (PIMs) and drug–drug interactions (DDIs) can significantly affect patient safety in the elderly, especially at transition of health care. Objective The aim of this study is to evaluate PIMs involved in potentially clinically significant DDIs in prescribed pharmacotherapy of elderly patients at hospital discharge. Setting Internal Medicine Clinic of University Hospital Dubrava, Zagreb, Croatia. Method During a 16-month period, the pharmacotherapy data were assessed using Lexicomp Online screening software to identify category C (monitor drug therapy), D (consider therapy modification) and X (avoid combination) DDIs. The European Union (EU)(7)-PIM criteria were applied to detect inappropriately prescribed medications involved in DDIs. Clinical pharmacists obtained data from patients’ medical records and patient/caregiver interviews. Main outcome measure The incidence of PIMs involved in potentially clinically significant DDIs. Results A total of 364 consecutive elderly patients were enrolled in the study. The mean number of prescription medications at discharge was 9.3. Overall, 2833 potentially clinically significant DDIs were identified: 2445 (86.3%) of them were category C, 347 (12.3%) category D and 41 (1.4%) were category X interactions. A total of 1164 PIMs were involved in 31.2% of category C interactions, 60.2% of category D interactions and 43.9% of category X interactions. The most frequent PIMs involved in potentially clinically significant DDIs were tramadol, benzodiazepines, moxonidine, vildagliptin and metoclopramide. Conclusion A very high incidence of DDIs in elderly patients and a high incidence of PIMs involved in DDIs was determined at hospital discharge.