Objective: The goal of this study was to clarify the effect of Helicobacter pylori (H. pylori) genotypes on CDX2 expression by detecting expression of CDX2 in H. pylori-positive gastric cancer (GC) and gastric intestinal metaplasia (GIM). Methods: CDX2 expression was evaluated by immunohistochemistry in 293 H. pylori-positive gastric tissues, including 38 cases of superficial gastritis (GS), 82 cases of GIM, and 173 cases of GC. The samples were subjected to PCR for detection and identification of cagA and vacA genes. Results: The frequency of the vacA genotypes vacA s1 (87.8%), vacA m2 (42.7%), vacA s1m2 (41.5%), cagA+ (75.6%), cagA+ vacA 51 (63.4%), cagA+ vacA m2 (34.1%), and cagA+ vacA s1m2 (32.9%) were higher than others in GIM. The frequency of the vacA genotypes vacA sl (63.0%), vacA m1 (37.0%), vacA s1m1 (25.4%), cagA+ (58.4%), cagA+ vacA 51 (39.9%), cagA+ vacA ml (28.3%), and cagA+ vacA s1m1 (21.4%) were higher than others in GC. CDX2 expression was decreased in genotypes vacA Si, vacA m1, vacA s1m1, cagA+, cagA+ vacA 51, cagA+ vacA m1, and cagA+ vacA s1m1 in the GC group (P < 0.05). CDX2 expression was higher in the age (> 60, P = 0.003), well differentiated (P < 0.001), and intestinal type GC (P < 0.001) groups than the other groups. The predominant genotypes were positive in poorly differentiated GC (P < 0.05). Conclusions: The predominant genotype was cagA+ vacA s1m2 in GIM, which was not associated with CDX2 expression; however, the predominant genotype was cagA+ vacA s1m1 in GC, which was negatively associated with CDX2 expression and differentiation.