Gestational Diabetes mellitus (GDM) results from an imbalance between insulin resistance and insulin secretion capacity during pregnancy. Tumor necrosis factor-alpha (TNF-α) is an inflammatory cytokine that is proposed to be involved in the pathogenesis of insulin resistance, and (CAPN10) has been detected as a susceptibility gene insulin resistance. The purpose of the present study was to recognize the impacts of the Tumor Necrosis Factor-alpha (-308 G/A) and CAPN10(-44 C/T, rs2975760) polymorphism on the development of GDM in the Saudi pregnant women population. We performed a case-control study and genotyped single nucleotide polymorphism of CAPN10(-44 C/T) gene and Tumor Necrosis Factor-alpha (-308 G/A) in 201 from the Western Saudi Arabia participants from Jeddah city including 101 patients with GDM and 100 normal (non-GDM). GDM and healthy subjects were genotyped with the PCR- RFLP technique. Heterozygocity for the gene polymorphisms did not occur more often in GDM women compared with non-GDM (TNF-alpha(-308 G/A): 41% versus 38%, p > 0.05; CAPN10(-44 C/T): 20% versus 17%; p > 0.05). Moreover, there was no outstanding difference between GDM and non GDM concerning homozygocity for (TNF alpha(-308 G/A) 5% versus 10%, p > 0.05); and CAPN10(-44 C/T) (2% versus 1%, p > 0.05). Contrary to the results of some other researchers, gene polymorphisms do not seem to be important in our population for the development of GDM. Tumor Necrosis Factor-alpha (-308 G/A) and CAPN10 (-44 C/T) genes are dependent on danger agents and might play roles in the risk of GDM.