Abstract Background High rates of tuberculosis (TB) in migrants from Tibet and Nepal have been documented for over 120 years and were previously ascribed to poor living conditions in the places of settlement. Adaptations to altitude involving genes in the Hypoxia-Inducible Factor pathway are present in 90–95% of Tibetans and in Nepalis these allele frequencies increase by 17% with each 1000 m increase in altitude. Methods We calculated the incidence of TB by country of origin in immigrants from South and East Asia in New South Wales (NSW), Australia between 2004 and 2018, and compared disease severity, site of infection, evidence of local transmission and prevalence of latent TB, among these groups. Results The incidence of active TB was consistently higher among 30 000 Nepalese and 1000 Tibetans than among all other immigrants to NSW. Nepal was the only country of origin where TB incidence in immigrants was not significantly lower than the reported TB incidence in the country of origin. Conclusions and implications High rates of TB among Nepalese and Tibetan immigrants in Australia are unlikely to be attributable to pre-existing disease or local acquisition. Phenotypic effects of high-altitude adaptations may include a dampening of inflammatory responses to hypoxia, an effect unmasked by descent to a normoxic environment. A corollary of these findings may be that hypoxia-induced inflammation limits TB progression, reconfirming previous explanations for the apparent efficacy of high-altitude sanatoria. If vindicated by subsequent research, these provisional findings could open new avenues into preventive and host-directed interventions for tuberculosis. Lay Summary The incidence of tuberculosis among Nepalese immigrants to Australia and other people of Tibetan heritage who migrate to lower altitudes is very high. In these screened populations, pre-existing active TB or locally acquired infection are unlikely explanations. We suggest that adaptations to altitude combined with descent to higher oxygen levels in air at sea level may be contributing factors.