Risk factors for COVID-19 death in high-altitude populations have been scarcely described. This study aimed to describe risk factors for COVID-19 death in three referral hospitals located at 3399 m in Cusco, Peru, during the first 14 months of the pandemic. A retrospective multicenter cohort study was conducted. A random sample of ~50% (1225/2674) of adult hospitalized patients who died between 1 March 2020 and 30 June 2021 was identified. Of those, 977 individuals met the definition of death by COVID-19. Demographic characteristics, intensive care unit (ICU) admission, invasive respiratory support (IRS), disease severity, comorbidities, and clinical manifestation at hospital admission were assessed as risk factors using Cox proportional-hazard models. In multivariable models adjusted by age, sex, and pandemic periods, critical disease (vs. moderate) was associated with a greater risk of death (aHR: 1.27; 95%CI: 1.14–1.142), whereas ICU admission (aHR: 0.39; 95%CI: 0.27–0.56), IRS (aHR: 0.37; 95%CI: 0.26–0.54), the ratio of oxygen saturation (ROX) index ≥ 5.3 (aHR: 0.87; 95%CI: 0.80–0.94), and the ratio of SatO2/FiO2 ≥ 122.6 (aHR: 0.96; 95%CI: 0.93–0.98) were associated with a lower risk of death. The risk factors described here may be useful in assisting decision making and resource allocation. © 2023 by the authors.