Introduction: Systemic lupus erythematosus (SLE) is a complex chronic autoimmune disease with heterogeneous features and multi-organ involvement such as skin, kidney, joints and heart causing a broad range of clinical manifestations. It is characterized by production of autoantibodies directed to diverse nuclear antigens, including double stranded DNA (dsDNA), ribonucleoproteins (RNP) and smith protein (Sm). Breakdown of immunological tolerance and environmental, genetic and hormonal factors contribute to the onset and severity of SLE. Toll-like receptor 9 (TLR9) is a member of TLRs, which belong a family of pattern recognition receptors, and it plays an important role in innate immunity. Several studies have found that polymorphisms in TLR9 gene are associated with SLE in different ethnic populations. Therefore, this study aimed to assess the relationship between TLR9 SNPs, rs352139 (+1174G/A) and rs5743836 (- 1237C/T), and SLE among Omani population. The specific aims of this study were to determine (1) the genotype and allelic frequency of TLR9 SNPs rs352139 and rs5743836 in Omani SLE patients and healthy control; (2) the association of TLR9 SNP genotypes with the risk of SLE; (3) the association of TLR9 SNP genotypes with APL antibodies; and (4) the association of TLR9 SNP genotypes with thrombocytopenia. Methods: The study population included two groups: 99 adult Omani patients who have been diagnosed with SLE and attending the Rheumatology Clinic at Sultan Qaboos University Hospital (SQUH) for follow-up and 96 apparently healthy volunteers. The whole blood was collected from each study participant, and genomic DNA was isolated. The gene segments containing TLR9 SNPs rs352139 and rs5743836 were amplified by polymerase chain reaction (PCR) using specific forward and reverse primers. The amplified DNA samples were sequenced using Sanger sequencing and their sequences were analyzed to identify TLR9 SNP genotypes. Results: There was no significant association between the TLR9 SNP rs352139 and rs5743836 genotypes and susceptibility to SLE in this study population. However, we found that rs352139 GG and rs5743836 CC genotypes were significantly associated with the occurrence of anti-cardiolipin (aCL) IgM (p=0.034 and p=0.028, respectively). In addition, rs352139 GG genotype was significantly associated with the thrombocytopenia (p=0.0078). In contrast, rs352139 AG genotype was significantly associated with protection from developing thrombocytopenia in SLE patients (p=0.0109). Furthermore, the study revealed that the presence of aCL antibodies was significantly associated with an increased risk of thrombocytopenia in SLE patients (p=0.036). Likewise, we found a significant association between the presence of anti dsDNA antibody and renal disorder among the SLE patients (p=0.013). Conclusion: TLR9 SNPs rs352139 and rs5743836 are not associated with the risk SLE among Omani population. However, the results suggest that both TLR9 SNPs may have an influence on aCL antibody production and rs352139 may affect the development of thrombocytopenia in Omani SLE patients.