To assess safety and immunogenicity, 213 healthy infants aged 6 weeks to 4 months were randomized to receive a single dose of placebo, a 10 4 or 10 5 p.f.u. dose of rhesus rotavirus (RRV) serotype 3, human—RRV reassortant (VP-7 serotypes 1, 2 or 4) or a 10 4 or 10 5 p.f.u. dose of tetravalent rotavirus vaccine (containing equal parts of serotype 1, 2, 3 and 4 strains). The infants were fed ad libitum before and after vaccination; no buffer was used. For 7 days after vaccination, potential vaccine side effects were monitored, and no significant differences were noted for any symptom evaluated among the single serotype, tetravalent or placebo groups. Sera, obtained before and 28 days after vaccination, were measured for antibody to rotavirus by IgG, IgA and IgM enzyme-linked immunosorbent assay in all subjects, and by neutralizing antibody to the individual serotypes by plaque reduction in placebo and tetravalent vaccinees. The serological response rates for serotypes 1, 2, 3, 4 and the tetravalent vaccine were 25, 12, 19, 11 and 22%, respectively, at 10 4 p.f.u.; 47, 50, 35, 29 and 61%, respectively, at 10 5 p.f.u.; and 37% for placebo. The tetravalent vaccine was more immunogenic at 10 5 than at 10 4 p.f.u. ( p = 0.04). Grouped together, the vaccines at 10 5 p.f.u. (single serotype and tetravalent) were more immunogenic than the vaccines at 10 4 p.f.u. (38 of 85 versus 17 of 94 seroresponders; p < 0.001). However, there was no difference between the serological response rates in the vaccine and placebo recipients as a consequence of the high seroconversion rate in the placebo group, which we postulate was produced by asymptomatic wild-type rotavirus infection. We conclude that a single dose of unbuffered rhesus or rhesus—human reassortant vaccine (VP-7 serotypes 1, 2, 3 or 4), or as a tetravalent preparation at 10 4 and 10 5 p.f.u. is safe but not adequately immunogenic and that asymptomatic wild-type rotavirus infections can occur year-round in the United States, affecting rotavirus seroresponsivity and its interpretation.