Background: HLA-G inhibits the immune system and has been linked to the risk and prognosis of numerous infectious diseases. Objective: to investigate the impact of HLA-G 14 bp insertion/deletion polymorphism on the susceptibility and severity of COVID-19. Methodology: This was a case-control study that comprised a total of 86 participants divided into two equal groups: 43 healthy controls and 43 COVID-19 Egyptian patients. Determination of the genetic polymorphism was performed for all study participants. Results: We found a statistically significant difference between both cases and healthy controls as regards the distribution of HLA-G genotypes (p-value=0.018). Healthy controls were 5.2 times more likely to have the INS/DEL genotype (OR= 5.2; 95% CI: 1.57-17.18) (p-value=0.007) and 2.7 times to have the INS/INS genotype (OR= 2.76; 95% CI: 0.76-9.96 (p-value=0.11). Although we found an association between HLA-G polymorphism and COVID-19 severity (p-value=0.002), however, it was not confirmed by logistic regression. The presence of the INS/INS genotype was linked to higher odds of developing severe COVID-19 (OR=3.66; 95% CI: 0.173-77.5) and (OR= 6.28; 95% CI: 0.577- 68.4) in comparison to the DEL/DEL and INS/DEL genotypes, respectively, but these higher odds were not statistically significant (p-value=0.40 and 0.13), respectively. Conclusion: Among healthy controls, the most common genotype was INS/DEL. The DEL/DEL genotype was associated with increased susceptibility to COVID-19 infection. HLA-G polymorphisms do not affect the severity of COVID-19.