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Background Medication reviews intended to identify drug-related problems (DRPs) have been researched in primary care, acute care and nursing homes rather than in long-term care hospitals (LTCHs). Objectives To assess the clinical impact of an interdisciplinary pharmacotherapy quality improvement and patient safety program in elderly patients with polypharmacy admitted to an LTCH. Setting An interventional, longitudinal, prospective study was conducted in a Spanish LTCH Method A total of 162 elderly (≥ 70 years) patients with polypharmacy (≥ 5 medications) were included. Pharmacist conducted the pharmacotherapy follow-up of patients (reconciliation, pharmacotherapeutic optimization, educational interviews) from admission to discharge. Demographic, clinical and treatment-related variables were recorded. Main outcome measured Clinical impact of the program by DRP-based effectiveness and drug-related morbidity (DRM)-based safety indicators. Results 895 DRPs (median of 5 (1-23)) were identified in 153 (94.4%) patients. The most common DRPs were unnecessary drug (25.3%), dosage too high (24.9%) and a need for additional drug (24.8%). The most frequent pharmacotherapy recommendations were individualizing the dosage regimen (29.6%) and stopping (27.3%) or starting (21.9%) a drug. The mean implementation rate of pharmacotherapy recommendations was 90.9%. The effectiveness indicator revealed a 94.9% of prevented or resolved DRPs. The safety indicator showed an 89.3% of prevented or resolved DRM. Therefore, the program prevented or resolved 92.5% of adverse effects and 91.7% of suboptimal responses or therapeutic failures. Conclusion This interdisciplinary patient safety program seems to be a valuable approach to identify, prevent and resolve the high number of DRPs and potential DRM that elderly patients with polypharmacy admitted to an LTCH present.