Background: Epidemiologic studies indicate that infections in early childhood may protect against pediatric acute lymphoblastic leukemia (ALL). Methods: We identified 3,402 ALL cases among children 0 to 5 years of age using the California Cancer Registry. From California birth records we randomly selected controls in a 20:1 ratio and frequency matched them to cases by birth year.Weinvestigated markers of exposure to infections, including month of birth, timing of birth in relation to influenza and respiratory syncytial virus (RSV) seasons, and birth order based on data from California birth certificates and national infection surveillance systems. Results: We observed an increased risk of ALL for spring and summer births, and for those first exposed to an influenza or RSV season at nine to twelve months of age compared with those exposed during the first three months of life, and this association was stronger among first born children [odds ratios (OR), 1.44 and 95% confidence intervals (CI), 1.13-1.82, for influenza exposure at nine to twelve months of age]. Decreased risk was observed with increasing birth order among non-Hispanic whites but not Hispanics (OR, 0.76 and 95% CI, 0.59-096, for fourth or higher birth order among whites). Conclusion: Our results support the hypothesis that infections in early childhood decrease risk of ALL. Impact: Our findings implicate early life exposure to infections as protective factors for ALL in young children.