Near the end of 2021, the COVID-19 Pandemic continues to create havoc worldwide, with predominance in the northern hemisphere by Nov 21, 2021. Popular belief stated that living under chronic hypobaric hypoxia would be correlated with higher COVID-19 severity. Despite the controversy, one of our forthcoming multinational publications gives significant scientific proof of a lower case fatality rate (CFR) at high altitude cities > 2,500 m as compared to the lowlands (< 1,000 m) in Bolivia, Peru, Colombia, Ecuador, and Mexico. It is crucial to determine what factors could be affecting this outcome, as they can provide the starting point for future research in COVID-19 and other possible viral pandemias’ management. We hereby provide possible explanations that could play a role in COVID-19 high-altitude protective behavior and we divide them into two branches. 1) The physiological (higher hemoglobin levels, higher erythropoietin levels, higher nitric oxide, lower arterial carbon dioxide levels, lower incidence of asthma and other comorbidities, lower number of ACE2 receptors, higher capillarity, cardio-vascular high altitude adaptation, lower incidence of asthma and other co-morbidities, increased mitochondrial effectivity, greater immunity, and lower coagulation pathologies in high-altitude inhabitants; and 2) the environmental (higher Ultra-Violet radiation, lower molecular density in the atmosphere, the absence of mosquitoes, and lower humidity). Further studies in all these areas are required to help face the Pandemic more efficiently.