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Recent experimental data show that exposure to microbes during early childhood can confer immunological tolerance and protect against Crohn's disease (CD). Epidemiological evidence for this link, however, remains controversial. Using prospective data, we examined the link between this hypothesis and risk for CD in children and young adults.A case-control study design was used. CD cases (diagnosed before age 20 years) were recruited from a tertiary-care pediatric hospital in Montreal, and population-based controls matched for age, gender and, geographical location were selected. Infection data were ascertained from physician-billing records. These records, which use International Classification of Diseases, Ninth Revision diagnostic codes, were consulted retrospectively but provide prospectively collected diagnostic information. Conditional logistic regression analysis was used to study potential associations. Odds ratios (OR) and 95% confidence intervals (95% CI) were estimated.Four hundred nine cases and 1621 controls were included. Regression analysis adjusting for potential confounding variables suggested that any recorded infection before the diagnosis of CD was associated with reduced risk of CD (OR, 0.67; 95% CI, 0.48–0.93). The protective effect was restricted to infections occurring mainly before 5 years of age, with increasing number of infections resulting in greater protection (1–5 infections: OR, 0.74; ≥6 infections: OR, 0.61; P value for trend = 0.039). Infections affecting the oral and upper respiratory tracts, cellulitis, and, enteric infections seemed most protective.Our study provides support for the hygiene hypothesis, whereby exposure to infections in early childhood could potentially reduce risks of CD.