ABSTRACT: HLA polymorphism is one of the genetic factors that may be associated with variations in susceptibility to COVID-19 infection. In this study, the frequency of HLA alleles among Saudi patients infected with COVID-19 was examined. The association with infection susceptibility and mortality was evaluated. This study included 135 Saudi COVID-19-infected patients (106 recovered and 29 died) who were admitted to hospitals because of their symptoms, and 135 healthy controls. HLA class I (A, B, C) and class II (DRB1, DQB1) genotyping was performed using the molecular method (PCR-rSSO). In this study, there was a significant increase in the frequency of HLA-A*01, B*56 and C*01 among infected patients compared to the control group (12.1% vs. 5.2%, p = 0.004, 3.7% vs. 0%, p = 0.006, 4.4% vs. 1.5%, p = 0.042, respectively). Moreover, there was a significant increase in the frequency of HLA-A*03 and C*06 among fatal patients compared to infected patients (13.8% vs. 5.7%, p = 0.036, 32.8% vs. 17.5%, p = 0.011, respectively). In terms of HLA class II, HLA-DRB1*04 was significantly higher in the control group compared to infected patients (27.4% vs. 16.3%, p = 0.002), while HLA-DRB1*08 was significantly higher in the infected group compared to the control (4.8% vs. 0.7%, p = 0.004). After statistical correction of the p value, A*01, B*56, DRB1*04 and DRB1*08 remained statistically significant (pc = 0.04, pc = 0.03, pc = 0.014 and pc = 0.028). This initial data suggested that individual HLA genotypes might play a role in determining susceptibility to COVID-19 infection and infection outcome. However, examining a larger sample size from different populations is required to determine a powerful association for clinical application.