This study assesses prevalence and patients characteristics related to polypharmacy in a sample of nursing home residents. We conducted a cross-sectional analysis on 4,023 nursing home residents participating to the Services and Health for Elderly in Long TERm care (SHELTER) project, a study collecting information on residents admitted to 57 nursing home in 8 countries. Data were collected using the interRAI instrument for long-term care facilities. Polypharmacy status was categorized in 3 groups: non-polypharmacy (0-4 drugs), polypharmacy (5-9 drugs) and excessive polypharmacy (≥ 10 drugs). Polypharmacy was observed in 2,000 (49.7%) residents and excessive polypharmacy in 979 (24.3%) residents. As compared with non-polypharmacy, excessive polypharmacy was directly associated not only with presence of chronic diseases but also with depression (odds ratio OR 1.81; 95% confidence interval CI 1.38-2.37), pain (OR 2.31; 95% CI 1.80-2.97), dyspnoea (OR 2.29; 95% CI 1.61-3.27), and gastrointestinal symptoms (OR 1.73; 95% CI 1.35-2.21). An inverse association with excessive polypharmacy was shown for age (OR for 10 years increment 0.85; 95% CI 0.74-0.96), activities of daily living disability (OR for assistance required vs independent 0.90; 95% CI 0.64-1.26; OR for dependent vs independent 0.59; 95% CI 0.40-0.86), and cognitive impairment (OR for mild or moderate vs intact 0.64; 95% CI 0.47-0.88; OR for severe vs intact 0.39; 95% CI 0.26-0.57). Polypharmacy and excessive polypharmacy are common among nursing home residents in Europe. Determinants of polypharmacy status include not only comorbidity but also specific symptoms, age, functional, and cognitive status.