The United Kingdom Childhood Cancer Study was designed to examine the relation between childhood cancer and preceding exposure to infectious diseases. The authors analyzed the relation between diagnosis (1991-1996) of acute lymphoblastic leukemia (ALL) at ages 2-5 years and clinically diagnosed infections in infancy. Almost all study children (96% of both cases and controls) were taken to a general practitioner for a non-immunization-associated visit at least once before their first birthday. Children diagnosed with ALL had significantly more clinically diagnosed infectious episodes in infancy than did controls; the average number of episodes was 3.6 (95% confidence interval (CI): 3.3, 3.9) versus 3.1 (95% CI: 2.9, 3.2). This case-control difference was most apparent in the neonatal period (< or =1 month); 18% of controls and 24% of ALL cases were diagnosed with at least one infection (odds ratio = 1.4, 95% CI: 1.1, 1.9; p < 0.05). Cases who had more than one neonatal infectious episode tended to be diagnosed with ALL at a comparatively young age; the mean age at ALL diagnosis was 37.7 months for cases with two or more episodes versus 45.3 months for cases with only one episode or none (p < 0.01). These findings support the hypothesis that a dysregulated immune response to infection in the first few months of life promotes transition to overt ALL later in childhood.