We evaluated the prevalence and factors associated with polypharmacy and investigated the role of polypharmacy as a predictor of length of hospital stay and in-hospital mortality. Thirty-eight internal medicine wards in Italy participated in the Registro Politerapie SIMI (REPOSI) study during 2008. One thousand three hundred and thirty-two in-patients aged ≥65 years were enrolled. Polypharmacy was defined as the concomitant use of five or more medications. Linear regression analyses were used to evaluate predictors of length of hospital stay and logistic regression models for predictors of in-hospital mortality. Age, sex, Charlson comorbidity index, polypharmacy, and number of in-hospital clinical adverse events (AEs) were used as possible confounders. The prevalence of polypharmacy was 51.9% at hospital admission and 67.0% at discharge. Age, number of drugs at admission, hypertension, ischemic heart disease, heart failure, and chronic obstructive pulmonary disease were independently associated with polypharmacy at discharge. In multivariate analysis, the occurrence of at least one AE while in hospital was the only predictor of prolonged hospitalization (each new AE prolonged hospital stay by 3.57 days, p < 0.0001). Age [odds ratio (OR) 1.04; 95% confidence interval (CI) 1.01-1.08; p = 0.02), comorbidities (OR 1.18; 95% CI 1.12-1.24; p < 0.0001), and AEs (OR 6.80; 95% CI 3.58-12.9; p < 0.0001) were significantly associated with in-hospital mortality. Although most elderly in-patients receive polypharmacy, in this study, it was not associated with any hospital outcome. However, AEs were strongly correlated with a longer hospital stay and higher mortality risk.