A prospective, 4-year cohort study of children born in an urban slum in northeastern Brazil was undertaken to elucidate the epidemiology of Cryptosporidium infection in an endemic setting, describe factors associated with Cryptosporidium-associated persistent diarrhea, and clarify the importance of copathogens in symptomatic cryptosporidiosis. A total of 1476 episodes of diarrhea, accounting for 7581 days of illness (5.25 episodes/child-year), were recorded: of these, 102 episodes (6.9%) were persistent. Cryptosporidium oocysts were identified in 7.4% of all stools, and they were found more frequently in children with persistent diarrhea (16.5%) than in those with acute (8.4%) or no (4.0%) diarrhea (P<.001). Low-birth-weight children and those living in densely crowded subdivisions were at greater risk for symptomatic infection. Disease course was highly variable and was not associated with the presence of copathogens. Recurrent Cryptosporidium infection and relapsing diarrhea associated with it were moderately common. In light of these data, the applicability of the current World Health Organization diarrheal definitions to Cryptosporidium-associated diarrheal episodes may need to be reconsidered.