Background: Studies have reported increased risks of pediatric acute lymphoblastic leukemia (ALL) among children born by cesarean delivery (CD). However, no previous study has examined the impact of CD on risk of infant leukemia specifically. Methods: In this study, 443 infants diagnosed with acute leukemia, including both ALL and acute myelogenous leukemia (AML), were identified at Children's Oncology Group institutions between January 1996 and December 2006; 324 controls frequency matched by year of birth were identified though random digit dialing and random selection from U.S. birth registries. Using interview data and, for a subset of participants, medical record data, we analyzed CD overall and by indications that likely resulted in pre-labor CD (PLCD) or emergency CD (ECD). Odds ratios (ORs) and 95% confidence intervals (CIs) for risk of ALL and AML were estimated using multivariable unconditional logistic regression models, adjusted for year of birth, birth weight, and maternal race. Results: We observed an increased point estimate for the association between CD and ALL (OR, 1.52 and 95% CI, 1.02–2.25). We did not observe an association between CD and AML (OR, 1.02 and 95% CI, 0.64–1.62). In analyses of indication for CD, we observed elevated effect estimates for the associations of both PLCD and ECD and infant ALL. Conclusions: Our analysis suggests an increased risk of infant ALL following CD, including both PLCD and ECD. Altered microbiota colonization may be involved in development of leukemia in infants, but clear biological mechanisms have yet to be determined. Impact: This study provides the first in-depth examination of CD and infant leukemia.