There have been reports showing a protective role of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) against gastrointestinal cancers. E-cadherin (CDH1) is an adhesion molecule involved in tumour invasion/metastasis. Silencing of CDH1 by promoter CpG island methylation was shown in gastric cancer, precancerous lesion, and Helicobacter pylori-infected chronic gastritis. We investigated the methylation status of CDH1 in noncancerous gastric mucosa in chronic aspirin user, and assessed its effect on methylation-associated carcinogenesis. Gastric mucosa samples from antrum were obtained from 217 cancer-free subjects, including 37 chronic aspirin users and 180 subjects with no history of chronic or occasional intake of aspirin. Methylation-specific polymerase chain reaction (PCR), i.e., MSP, was performed for CDH1 gene promoter. In all 217 subjects, CDH1 methylation was detected for 69 subjects (31.7%). CDH1 methylation more frequently occurred in H. pylori-infection-positive subjects (P < 0.0001), while chronic aspirin users had a significantly lower risk of CDH1 methylation [nonuser versus user 36.1% versus 10.8%; odds ratio (OR) = 0.21, 95% confidence interval (CI) = 0.07-0.63, P = 0.005]. Logistic regression analysis showed that chronic aspirin use was the independent factor for lower risk of CDH1 methylation (adjusted OR = 0.21, 95%CI = 0.07-0.66, P = 0.008). Chronic aspirin use was associated with lower risk of CDH1 methylation in H. pylori-positive subjects (nonuser versus user 49.5% versus 19.0%; OR = 0.24, 95%CI = 0.08-0.76, P = 0.01). Similar trend was also found in H. pylori-negative subjects (P = 0.07). No association was found between CDH1 methylation status, and duration and dose of aspirin. Our data suggest that chronic aspirin use is associated with reduced risk of CDH1 methylation in human gastric mucosa. Aspirin may have suppressive role against methylation-related gastric carcinogenesis.