Abstract Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has emerged as a global pandemic. This viral disease primarily causes lung pneumonia and has a wide range of clinical manifestations. The severity of infection ranges from those who are asymptomatic or with mild symptoms which do not require hospital admission, to those who require ventilator support and eventually die, depending on immunity, age and other comorbidities existing with the patients. The present report is an attempt to study the effect of physiological and environmental factors existing at high altitudes (HA) with spread of SARS-CoV-2 infection. Analysis of existing data revealed that HA natives do possess certain physiological advantages such as (1) improved hypoxic ventilatory response, (2) higher concentration of oxygen carrying molecules, haemoglobin, (3) increased production of Vitamin D, due to intense solar radiation, (4) lower rates of comorbidities such as lung infections, obesity etc. and (5) most importantly reduced production of angiotensin converting enzyme 2, a carrier molecule for SARS-CoV-2 virus entry into the host cell; all of which can collectively account for improved tolerance to SARS-CoV-2 infection in HA natives. In addition, environmental factors at HA such as (6) dry and chilly winds, (7) low air density and (8) intense UV radiations may further inhibit viral growth and spread into the atmosphere. We thus conclude that, high altitude natives may posses physiological and environmental advantage over low landers in terms of reduced severity of SARS-CoV-2 infection and its limited spread. Graphic abstract Gift factors associated with COVID-19 spread at high altitude.