Typhoid fever remains an important public health problem in many areas of the world and an effective, non-reactogenic vaccine would be useful to control this disease. An attenuated Salmonella typhi strain (Ty21a), which has shown promise in previous trials, was evaluated in a controlled field trial in Santiago, Chile. In this trial, 82,543 schoolchildren were randomly assigned to receive one or two doses of Ty21a vaccine in enteric-coated capsules or placebo. The enteric-coated vaccine formulation was well tolerated and practical for mass oral immunization. In the first two years of surveillance, 213 cases of bacteriologically-confirmed typhoid fever were found in schoolchildren participating in the trial; annual rates in the placebo group were 139 and 227 per 100,000. Vaccine efficacy in the first two years after vaccination was 59% for two doses and 29% for one dose; no efficacy was found 3-5 years after vaccination. These results indicate that it will be necessary to identify a vaccine formulation and schedule for Ty21a S. typhi that is practical and provides high level protection for greater than 2 years.