In a case-cohort study of early-onset sepsis, antibiotic resistance was more likely for infections in neonates born to mothers who were given antibiotics during pregnancy (odds ratio 4.6; 95% confidence interval: 1.1-19;P = 0.05). Risk of resistance increased with duration of antibiotics and number of antibiotic courses during pregnancy. Preterm birth and hospitalization during pregnancy were also associated with resistance. These risk factors should be considered when selecting empiric antibiotics for therapy of early-onset sepsis in infants.