Gastric cancer is the fourth most common cause of malignancy death in the world, which also has a high prevalence in Iran. CASPASE 3 GENE is considered as one of the major GENEs related to gastric cancer. The present study aimed to investigate the relationship between rs12108497 polymorphism of CASPASE 3 GENE. Due to the fundamental role of CASPASEs, we have considered an SNP of CASPASE 3 (common to two-way joint execution CASPASEs), which has been proven to be related to various cancers. In this case-control study, 95 patients and 90 healthy subjects were enrolled. The patient status was approved, by endoscopy and pathology, to be gastroduodenal adenocarcinoma. Overall, 5 ml of the peripheral blood was collected from all participants, after obtaining an informed consent. Genomic DNA was extracted using the salting-out method and genotypic polymorphism was investigated using the PCR-RFLP method. The frequency of rs12108497 polymorphism was significantly different between patients with gastric adenocarcinoma and healthy subjects (p = 0. 0259). Also, the difference in the distribution of T/T genotype was significant (P = 0. 0111) and according to the OR score ((95. 1% CI = 1. 3539-10. 5412) and OR = 3. 7778), it is suggested that the T/T genotype increases the risk of disease. Our results confirm the association between the rs12108497 polymorphism of CASPASE 3 GENE and the increased risk of gastric adenocarcinoma in individuals referring to Toba Sari Clinic.