Background. SARS-CoV-2 has affected every demography disproportionately, in-cluding even the native highland populations. Hypobaric-hypoxic settings at high -altitude (HA, >2,500 masl) present an extreme environment that impacts the survival of permanent residents, possibly including SARS-CoV-2. Conflicting hypotheses have been presented for COVID-19 incidence and fatality at HA. Objectives. To evaluate protection or risk against COVID-19 incidence and fatality in humans under hypobaric-hypoxic environment of high-altitude (>2,501 masl). Methods. Global COVID-19 data of March 2020-21, employed from official websites of the Indian Government, John Hopkins University, and Worldometer were clustered into 6 altitude categories. Clinical cofactors and comorbidities data were evaluated with COVID-19 incidence and fatality. Extensive comparisons and correlations using several statistical tools estimated the risk and protection. Results. Of relevance, data analyses revealed four distinct responses, namely, partial risk, total risk, partial protection, and total protection from COVID-19 at high-altitude indicating a mixed baggage and complexity of the infection. Surprisingly, it included the countries within the same geographic region. Moreover, body mass index, hypertension, and diabetes correlated significantly with COVID-19 incidence and fatality rate (P <= 0.05). Conclusions. Varied patterns of protection and risk against COVID-19 incidence and fatality were observed among the high-altitude populations. It is though premature to generalize COVID-19 effects on any particular demography without further extensive studies.