The objective of the study was to define the characteristics and microbiology of persistent diarrhea (PD) in US children. Six-month prospective cohort study of a convenience sample of 604 healthy 6- to 36-month-old children recruited by the Slone Center Office-based Research Network. Of 611 diarrhea episodes, 50 (8.2%) lasted < or = 14 days. The incidence of PD was 0.18 episodes per person-year, and the median duration of episodes was 22.0 days (range, 14-64 days). PD episodes were more likely than acute episodes to result in a medical visit (28.0% vs 8.2%; P = 0.0001). The most commonly used treatments were oral rehydration solution (12.0% of episodes) and antibiotics (6.0%). No bacterial or parasitic pathogens were associated with PD; but norovirus, rotavirus and sapovirus were each significantly more prevalent in PD stools compared with baseline stools, with relative risks of 12.4, 6.9 and 6.2, respectively. Fifty-nine per cent of the PD specimens tested were negative for all studied pathogens. PD occurs with a frequency of approximately 1 case per 5 person-years in US infants and young children. It seems to be a generally benign illness, with only 28% of cases presenting to medical care. Although viral pathogens seem to cause a minority of PD episodes in this population, most are not due to currently known infectious agents.