The COVID-19 pandemic is characterized by spatial heterogeneity in prevalence, morbidity, severity, and mortality rates in different human populations. Although environmental, demographic (i.e., age and gender) and clinical factors (i.e., comorbidities) cannot be excluded, heterogeneity in the genetic makeup of individuals of different races and ethnicities could be a contributing, and perhaps a decisive, factor in the observed variations in the frequency and severity of cases. Recently, several hypotheses have proposed a role for single-nucleotide polymorphisms (SNPs) in the gene encoding the viral receptor (ACEII) expressed on cell surfaces and the transmembrane serine protease (TMPRSS2) involved in the pathogenicity of the virus via cleaving the viral spike protein and facilitating the binding of the latter to its receptor. This study comes as a contribution to identifying the genetic makeup that may be associated with the spread of COVID-19 and severity of the disease in healthy Syrian subjects well as individuals diagnosed with diseases related to severity of the disease. We investigated the frequency of two SNPs; rs8134378 (G>A) and rs12329760 (C>T) in the TMPRSS2 gene. We designed and performed a PCR using specific primers for the site of each of the two SNPs, followed by sequencing of the amplification products to identify nucleotide change for each. Our findings revealed a high frequency of the rs8134378 "A" minor allele in the healthy subjects (11.4%) and male patients (17.9%), and in contrast a low frequency of the rs12329760 "T" allele in healthy subjects (19%) and male patients (16.7%), compared with the average frequencies of (7.7%) and (22.5%), respectively, in other populations in the world. Nevertheless, all these observed differences were not statistically significant (p >0.05 for all comparisons). Our results suggest a possible association between the frequencies of both polymorphisms in the population studied and the reported low rates مقال بحثي SJSI The Frequency of Rs8134378 and Rs12329760 Gene Polymorphism in A Cohort of Healthy and Compromised Syrians تواتر التعددين الشكليين 8134378rs و 12329760rs في جين 2TMPRSS لدى جمهرة من األصحاء والمرضى السوريين SJSI – 2023: VOLUME 1-1 Research Article: Aljamali & Youssef 2 of severe morbidity and mortality in the Syrian population. The major limitation of this study is the relatively small size of its population. Key Words: TMPRSS2 gene, Syrians, prevalence, SNP, rs8134378, rs12329760.