Introduction: Polypharmacy is frequent in older adults. The association between polypharmacy and mortality is controversial due to the difficulty of controlling confounding factors such as comorbidity or gender. Objective: The main objective of this study was to demonstrate the association between polypharmacy and mortality in older adults. The secondary objective wasto determine the role of sex and comorbidity on the association between polypharmacy and mortality. Material and Methods: A retrospective, analytical, observational cohort study was conducted. A database of an outpatient geriatric clinic in a military hospital in Peru was analyzed. Outpatients ≥ 60 years of age were included. Polypharmacy was defined as the consumption of ≥ 5 drugs for ≥ 90 days. Cox regressions adjusted for age, marital status, cognitive impairment, physical frailty, functional dependence, and number of comorbidities were performed. Subgroup analyzes were performed for the risk of death from polypharmacy, stratified by sex and presence of comorbidity. Results: Polypharmacy increased the risk of mortality. The Hazard Ratio adjusted for sex was 15,16 (1,80-21,66) and 5,55 (2,90-10,06) for women and men, respectively. The Hazard Ratio in non-comorbid patients was 1,94 (1,17-2,05; CI=95 %). Conclusions: Polypharmacy is a risk factor for mortality regardless of the sex and comorbidities of the patient.