Epidemiological studies have reported the relationship between vacuolating cytotoxin A (vacA) s-/m- region genotypes and duodenal ulcer (DU), but the results remained inconclusive. We performed the present meta-analysis to investigate a more authentic association between vacA s-/m- region genotypes and DU. Literature search was performed by searching Embase, PubMed and ISI Web of Science databases as well as checking references from identified articles, reviews and the abstracts presented at related scientific societies meetings. The association was assessed by combined odds ratio (OR) with 95% confidence interval (CI). A total of 42 studies were included in our final meta-analysis. The combined ORs (95% CIs) showed that vacA s1 (OR = 2.96, 95% CI = 2.34-3.75), m1 (OR = 1.46, 95% CI = 1.05-2.04) and s1m1 (OR = 1.89, 95% CI = 1.47-2.42) were associated with increased DU risk significantly in the overall studied population. Subgroup analyses by ethnicity showed that vacA s1 increased the risk of DU in Asian countries (OR = 1.92, 95% CI = 1.30-2.83), European countries (OR = 3.58, 95% CI = 2.13-6.03) and Latin American countries (OR = 4.20, 95% CI = 2.21-7.98); vacA m1 increased the risk of DU in Latin American countries (OR = 2.98, 95% CI = 1.59-5.56); vacA s1m1 increased the risk of DU in Asian countries (OR = 2.04, 95% CI = 1.12-3.73) and Latin American countries (OR = 2.05, 95% CI = 1.20-3.48); vacA s2m1 increased the risk of DU in Latin American countries (OR = 2.30, 95% CI = 1.17-4.50). The data suggest that genotype testing of vacA s- and m- region will be useful in screening susceptible individuals for DU development.