The p53 gene has been referred to as 'the guardian of the genome' because it controls apoptosis and cell cycle arrest. The purpose of this study was to evaluate the association of p53 codon 72 genetic polymorphism and the p53 immunohistochemistry with Helicobacter pylori-associated gastroduodenal diseases, including gastric cancer. This study included 1,852 subjects: controls and patients with gastric cancer, dysplasia, benign gastric ulcers, and duodenal ulcers (DU). Biallelic polymorphism was genotyped by restriction fragment length polymorphism. Immunohistochemical analysis for the detection of mutant type p53 expression was performed. The frequency of the Pro/Pro allele of the p53 codon 72 was higher in the patients with H. pylori-positive dysplasia than in controls (OR: 2.3, 95% CI: 1.3-4.3), but it was less frequent among patients with a H. pylori-positive DU (OR: 0.5, 95% CI: 0.3-0.8). However, there was no significant association with gastric cancer, including the location, stage, or histological type of gastric cancer. Expression of a mutant type of p53 protein was detected in 6.3% of dysplastic tissues and 26.5% of cancerous tissues compared 0% in the controls. Positive expression was higher in the intestinal type of cancer (34.9%) than in the diffuse type (15.0%; P = 0.001). These results suggest that genetic polymorphism of p53 codon 72 played a role in the determination of H. pylori-associated gastroduodenal diseases, but p53 immunostaining did not correlate with those of the p53 genetic polymorphism analysis.