We evaluated enteric infection serology as an alternative outcome measure to diarrhea prevalence in a randomized controlled trial of household-based drinking water treatment; 492 households were randomly assigned to 5 household-based water treatment interventions or control. Individuals were followed weekly over 52 weeks to measure diarrhea prevalence. Study subjects of age <or= 6 months and < 24 months had blood drawn at entry and exit from the study or age cohort. Serologic assays for Cryptosporidium parvum, Giardia intestinalis, enterotoxigenic Escherichia coli (ETEC), and Norovirus were done. Of 343 subjects eligible for the study, the proportions of subjects experiencing serologic responses were 56% for Norovirus, 24% for C. parvum, 10% for ETEC, and 16% for G. intestinalis. Serologic response was associated with increased diarrhea prevalence only for G. intestinalis (P = 0.0134). Serologic response to the antigens tested for G. intestinalis but not for Norovirus, C. parvum, and ETEC may be a useful health-effect measure. Larger intervention studies that yield a more marked effect on diarrheal disease, use additional and improved serologic assays, and that collect serum samples at more frequent intervals are needed.