In an effort to describe the natural history of enterotoxigenic Escherichia coli (ETEC) infection and diarrhea, 200 children in Guinea-Bissau, West Africa, were followed up from birth until up to age 2 years with weekly stool specimen collection, regardless of whether the children had diarrhea. ETEC isolates were tested for the presence of the porcine and human heat-stable toxins (STp and STh), the heat-labile toxin (LT), and 18 of 21 known colonization factors (CFs). The rate of primary infections increased substantially after age 3 or 6 months (depending on the type of ETEC causing the infection). The pathogenicity of STh-containing ETEC was substantially higher than that of STp-containing ETEC, and STp and STh were associated with separate sets of CFs. Small epidemics were observed, mainly caused by STh-containing ETEC. The difference in epidemic propensity, CF association, and pathogenicity suggests that STh- and STp-containing ETEC represent 2 different groups of human ETEC. Vaccines should primarily target STh-containing ETEC.