Abstract Background: Childhood infection and immune response have long been suspected in the etiology of childhood leukemia, specifically acute lymphoblastic leukemia (ALL). Normal primary inoculation of the core human microbiome is circumvented by cesarean section (CS) delivery, which is a proposed modulator of both immune response and early-life infection. Methods: In this study, we examined CS delivery and the risk of childhood leukemia using data from the California Childhood Leukemia Study (CCLS) case–control study and additive logistic regression models. Results: We observed no association between CS and acute myelogenous leukemia [OR, 0.96; 95% confidence interval (CI), 0.52–1.55]. We observed a suggestive association for ALL and CS (OR, 1.22; 95% CI, 0.97–1.54). When examining common ALL (cALL), defined as ALL with expression of CD10 and CD19 surface antigens and diagnosis occurring between 2 and 5.9 years of age, we found a significant association with CS (OR, 1.44; 95% CI, 1.0–2.06). ALL subjects that are not cALL showed a similar risk as ALL overall (OR, 1.15; 95% CI, 0.91–1.44). Because of previous findings suggesting effect modification, we stratified cALL subjects by Hispanic status. Although we observed no relationship for CS in non-Hispanics (OR, 1.14; 95% CI, 0.72–1.79), we did observe a strong association between cALL and CS in Hispanics (OR, 2.34; 95% CI, 1.23–4.46). Conclusion: Within the CCLS, CS delivery seems to be associated with cALL and Hispanic subjects may be driving the association. Impact: Further research combined with investigations into response to early infection and the microbiome is warranted. Cancer Epidemiol Biomarkers Prev; 23(5); 876–81. ©2014 AACR.