BACKGROUND: When delivered through vaccination Vi-polysaccharide antigen of Salmonella enterica serotype Typhi protects against typhoid by inducing IgG anti-Vi antibodies. We aimed to determine whether the presence of antibodies following natural infection is associated with a lower incidence of typhoid fever in endemic regions. METHODS: We analyzed data from a cohort study of typhoid fever conducted in Dhaka, Bangladesh. Plasma IgG anti-Vi antibodies were measured using a standard enzyme-linked immunosorbent assay in random serosurveys of a population that had not previously received typhoid vaccination. Participants were followed for up to 20 months for culture-confirmed typhoid fever. The receiver operating characteristic (ROC) curve and Cox proportional hazard models were used to evaluate the associations between antibody levels and typhoid risk. RESULTS: The ROC analysis revealed that IgG anti-Vi antibody titers were predictive of typhoid risk among the 8,261 serosurvey participants (area under the curve: 0·63; 95% confidence interval (CI): 0·58─0·67). Detection of any antibodies was associated with a lower risk of typhoid in crude analyses (hazard ratio (HR): 0·13; 95% CI: 0·03─0·52), though this association declined after adjustment (HR: 0·32; 95% CI: 0·07─1·40). A positive correlation was observed between IgG anti-Vi titers and age (correlation coefficient 0·35; p