Objective: The aim of this study was to investigate the impact of sex-specific genetic factors in the pathogenesis and prog- nosis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV2)-induced macrophage activation syndrome (MAS), independent of age and comorbidity presence. Materials and Methods: Patients aged 18–50 years who had been diagnosed with coronavirus 2019 (COVID-19), the disease caused by the SARS-CoV2 virus, were enrolled in a prospective, case-control, multi-center study. Genetic alterations and messenger RNA (m-RNA) expression levels of the TLR7, TLR8, ACE2, CD40L, CXCR3, and TASL genes were determined using DNA sequencing analysis, and gene expression was determined using quantitative reverse transcriptase polymerase chain reaction testing. PolyPhen-2 (Polymorphism Phenotyping v2; Adzhubei et al., 2010) and SNAP2 (Rostlab, Munich, Germany) genetic analysis tools were used to define the pathogenic effects of detected mutations by sequencing the selected genes in hotspot regions. Results: The study group consisted of 80 patients diagnosed with COVID-19 and was divided into groups based on sex and MAS status. Twenty-nine mutations were detected in 6 genes. Among the alterations, 15 were identified in this study for the first time and 9 were pathogenic. Pathogenic missense mutations in the TLR7, TLR8, ACE2, and TASL genes were detected in the MAS (+) group. In males, decreased TLR7, TLR8, and CXCR3 expression was statistically significant in the MAS (+) group (p<0.050). CXCR3 expression was lower in the female and male MAS (+) groups compared with the MAS (-) groups (p<0.050). Conclusion: In the absence of major risk factors for COVID-19, the TLR7/8, ACE2, and CXCR3 variants and decreased m-RNA expression levels associated with genetic susceptibility may be independent prognostic risk factors for COVID-19.