Background: Single nucleotide polymorphisms (SNPs) in the D-Loop region of mitochondrial DNA (mtDNA) have been implied in tumorigenesis of different types of tumors, but the associations involving polymorphisms in mtDNA coding regions still need to be clarified. This study aimed to identify SNPs of mitochondrial cytochrome c oxidase genes (MT-CO) in the occurrence of gastric cancer (GC). Methods: The MT-CO genes were sequenced between 170 GC patients and 174 matched healthy controls. The chi(2) test was used to analyze differences in SNP frequencies between the two groups. Results: The SNPs of MT-CO region were associated with the risk of GC. The genotype 9540T was significantly associated with an increased risk for GC (P=0.018), whereas 9548G was associated with a reduced risk (P=0.029). Conclusions: The SNPs in MT-CO genes were found to be risk biomarkers for GC. It may provide a novel insight into the molecular mechanism in GC tumorigenesis and progression.