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OBJECTIVES To evaluate whether STOPP/START v2 potentially inappropriate medications (PIMs) and potential prescribing omissions (PPOs) are associated with 6-month mortality and unplanned hospitalization in hospital-discharged older patients. DESIGN Multicenter prospective cohort observational study. SETTING AND PARTICIPANTS Patients aged ≥65 years consecutively discharged from acute geriatric and internal medicine wards of 2 teaching hospitals in northwestern Italy. METHODS At discharge, a comprehensive geriatric assessment was performed in each patient, prescribed medications were recorded, and PIMs and PPOs were determined according to STOPP/START v2. Death and unplanned readmissions at 6 months were investigated through telephone interviews; variables associated with outcomes were identified in the overall sample and according to discharge setting [ie, home vs medium/long-term care facility (MLTCF)] through a multivariate logistic regression model. RESULTS Among 611 patients (mean age 81.6 years, 48.4% females, 34.2% MLTCF-discharged, mean number of drugs 7.7 ± 3.2) with a potentially inappropriate prescription (PIP) prevalence at discharge of 71.7% (PIMs 54.8%, PPOs 47.3%), mortality and unplanned readmission rates were 25.0% and 30.9%. Neither PIMs nor PPOs were associated with overall mortality. A higher number of PIMs was significantly associated with unplanned readmission in the overall sample [odds ratio (OR) 1.23, 95% confidence interval (CI) 1.03-1.46] and in home-discharged patients (OR 1.38, 95% CI 1.13-1.68). The number of drugs at discharge was associated with unplanned readmissions in the overall sample (OR 1.11, 95% CI 1.05-1.18) and in MLTCF-discharged patients (OR 1.27, 95% CI 1.13-1.42). PPOs were not significantly associated with clinical outcomes. CONCLUSIONS/IMPLICATIONS In hospital-discharged older patients with polymorbidity, 6-month unplanned readmissions were associated with a higher number of PIMs in home-discharged patients and with number of drugs in MLTCF-discharged patients. This reaffirms the importance of performing a systematic and careful review of medication appropriateness in hospital-discharged older patients.