Orally administered live rhesus monkey rotavirus vaccine (RRV, VP7 serotype 3) and human-rhesus reassortant rotavirus vaccine (DxRRV, VP7 serotype 1) were evaluated in a placebo-controlled field trial of 223 infants 2-4 months old. Both vaccines were mildly reactogenic but were generally well tolerated in the 10 days after vaccination. RRV and DxRRV were immunogenic, inducing serum antibody responses in 78% and 71% of the vaccines, respectively. Efficacy of RRV vaccine was 66% (P = .01) and of DxRRV vaccine 77% (P = .002) against rotavirus-associated illness in the first season after vaccination. Efficacy of RRV vaccine against rotavirus-associated illness over three rotavirus seasons was 51.2% (P = .045) and of DxRRV vaccine was 67.3% (P = .006). RRV vaccine provided heterotypic protection of 58.5% (P = .041) and DxRRV vaccine provided homotypic protection of 72.8% (P = .005) over three seasons against the predominant serotype 1 rotavirus.