Background: Drug-related problems (DRPs) have been shown to prevail in hospitalized patients, and polypharmacy and increasing age have been identified as two important risk factors. Objective: We investigated the occurrence of DRPs and adverse drug reactions (ADRs) amongst hospitalized patients prescribed polypharmacy, and the association of advanced age and female gender. Method: A retrospective cross-sectional study was performed in an acute-care hospital in Singapore. Only patients prescribed polypharmacy were included. Mann-Whitney test was used to test for significant difference between the age and gender of patients and their risk of acquiring DRPs. The relative risks of developing DRP and ADR for geriatric patients and female patients were estimated. Results: Of 347 patients prescribed polypharmacy (43% female and 58.2% geriatrics), no statistical correlations were observed between age and gender with developing DRPs. An increased number of medications was associated with higher risk for patients with DRPs on admission (p = 0.001), but not for inpatients with DRPs (p = 0.119). Results from patients with ADRs showed that the relative risk (RR) of geriatrics prescribed polypharmacy and major polypharmacy (10 and more drugs) were 1.01 and 1.23, respectively. Female patients had a RR of 0.79 compared with male patients in developing ADRs. Conclusion: Results showed that among patients with polypharmacy, age and gender may not be as important as number of drugs prescribed as predictors of experiencing a DRP. A similar trend was observed in the development of ADRs.