Entamoeba histolytica infection and colitis occurred in 55% and 4%, respectively, of a cohort of Bangladeshi preschool children observed for 2 years. DNA typing demonstrated that infecting E. histolytica isolates were genetically diverse. Innate resistance to infection in children was linked to the absence of serum anti-trophozoite IgG. Most children who lacked serum anti-trophozoite IgG failed to develop it in response to a new infection. The serum anti-trophozoite IgG response clustered in families, which is consistent with genetic inheritance. Acquired resistance to infection was linked to intestinal IgA against the carbohydrate-recognition domain of the E. histolytica galactose N-acetyl-d-galactosamine lectin. This was associated with an 86% reduction in new infection over 1 year. Amebiasis is a common and potentially serious infection in children from Dhaka, and both innate and acquired immune responses limit infection.