Intriguing epidemiological observations suggest, and biological evidence supports, an inverse correlation between increasing HbE/thalassemia trait prevalence rates and decreased susceptibility to, and fatality from, COVID-19 infections (Table 1, Figures 1, 2). Local COVID-19 infections within Thailand vary 6-fold between the northeast (2.84% of total cases) versus the south (19%), in tandem with regional variations in HbE gene frequency (70% in the northeast compared to 12% in the south) [3,13,25]. Similarly, Malaysia, which borders southern Thailand, has an HbE trait frequency of only 3.8% [26] but reports substantially higher COVID19 infections compared to Thailand [4]. Interestingly, in Cambodia and Laos (where zero COVID-19 deaths are reported) (Table 1), thalassemia mutation rates are similar to Thailand [13]; for Cambodia, the thalassemia prevalence is 62.7% (HbE being the most prevalent, at 56%) [27]. In Myanmar (HbE carrier rates vary between 1.9 and 42% depending on ethnic group and geography), low infection and death rates are also seen (Table 1) [28]. Vietnam and the neighboring Chinese province of Yunnan both report low COVID-19 infection rates, with locally high prevalence of HbE trait in line with other mainland SE Asian nations (Table 1) [15–24,29–31]. In Vietnam, the Mon-Khmer-speaking ethnic groups are genetically closer to the Thai-Lao-Cambodian border populations and report HbE gene prevalence up to 36% [29]. Singapore, where the prevalence of β-thalassemia trait is 0.9% and HbE trait is 0.55% [32], was severely hit by COVID-19 compared to neighboring Thailand, but the death rates were very low [4]. The high number of cases in Singapore seems to stem from clusters in male migrant workers living in close proximity in crowded living quarters, promoting higher infectious spread [33]. These migrant workers are from various ethnic groups (e.g., Bengali and Tamil) with higher HbE/thalassemia trait prevalence but also higher glucose-6-phosphate dehydrogenase (G6PD) deficiency rates, compared to resident Singaporeans [32,34,35]. G6PD-deficient patients have been shown to be highly susceptible to enteroviruses, human dengue virus, and human coronavirus 229E infection. They also tend to develop severe pneumonia after microbial infection [36]. Consequently, close proximity overrides the protective effects of HbE and/or selectively potentiates the risk to infect the ones without the hypothetically protective trait, especially from patients carrying a higher viral load. Thailand’s and Singapore’s effective 14-day quarantine policy of all arrivals have now virtually eradicated local COVID-19 cases [37]. In the remainder of SE Asia and South Asian territories, the trend continues with increasing COVID-19 infection and death rates where HbE/thalassemia trait prevalence is low (Table 1, Figures 1, 2) [14–23]. In Brazil, a country severely hit by COVID-19, despite heavy early Italian migrations, less than 2% of Brazilian blood donors exhibit hemoglobinopathies [38]. Similarly, Spain, also severely affected by COVID-19, has a thalassemia trait of only 0.92% [39]. Despite its higher thalassemia trait prevalence, Italy was severely hit by COVID-19, initially in Lombardy, with a traditionally low carrier rate compared to islands and coastal areas [40]. Greece [40] and Cyprus [41], with an effective lock-down, a distancing strategy, and a higher, homogenous carrier rate, seem to be experiencing lower COVID-19 rates compared to their European peers, even during the second wave (Table 1, Figures 1, 2).