The degree of protection conferred by natural rotavirus infection was estimated through analyses of data gathered as part of a 2-year rotavirus vaccine study of 1185 Native American infants. In 292 placebo recipients with complete serum sample sets, rotavirus IgA antibody indicative of infection before 2 months of age was associated with a 58% decrease in symptomatic infections throughout the trial. In all 391 placebo recipients, the preventive effectiveness of an initial symptomatic infection was 72% overall and 94% within 6 months following the infection. In contrast to studies conducted at other sites in the United States, serotype G3 was the predominant serotype associated with gastrointestinal episodes (80%). The effectiveness of an initial serotype G3 episode with respect to preventing subsequent serotype G3 episodes was 91%.