Increased expression of reactive oxygen species modulator 1 protein-triggered reactive oxygen species production was reported in the mitochondria of various cancer cell lines. To date there is no report on association between Romo1 gene polymorphisms and gastric cancer risk. To investigate the relationship between Romo1 gene polymorphisms and GC risk, we conducted a case-control study in a population from northwest China (358 GC patients and 412 healthy controls). The genotypes of two SNPs were determined with PCR-denaturing high-performance liquid chromatography and direct DNA sequencing. We found that the genotype and allele distributions of two polymorphisms were significantly different in GC patients compared with controls, When the wild type of two loci were served as the reference group, respectively, significantly increased risk for gastric cancer were associated with rs6060566 TC genotype (Adjusted OR = 1.525, 95 % CI =1.126-2.138), rs6060567 GC genotype (Adjusted OR = 1.641, 95 % CI =1.238-2.291) and CC genotype (Adjusted OR = 1.594, 95 % CI =1.102-2.973). This effect was more pronounced in patients with smoking, alcohol consumption, H.pylori infection,and male patients subgroups. Haplotypes analysis of two genetic variants showed that the most common haplotype TG displayed the strongest evidence of association with GC (corrected P = 9.30 × 10(-5)), and was associated with protection against GC (OR = 0.584). Whereas the CC haplotypes had significant correlation with GC risk (OR = 1.732). These findings suggested genetic polymorphisms of Romo1 gene were associated with significant risk of GC in Northwestern Chinese population, which is strengthened by alcohol use, smoking, H.pylori infection or male patients.