Objective: To assess the association between early empirical antibiotics and neonatal adverse outcomes in very preterm infants without risk factors of early-onset sepsis. Study design: This is a secondary analysis of the EPIPAGE-2 study, a prospective national population-based cohort that included all liveborn infants at 22-31 completed weeks of gestation in France in 2011. Infants at high risk of early-onset sepsis (born after preterm labor or preterm premature rupture of membranes, or from mother who had clinical chorioamnionitis or received antibiotics during the last 72 hours) were excluded. Early antibiotic exposure was defined as antibiotics started at Day 0 or Day 1 of life, regardless of the duration and type of antibiotics. We compared treated and untreated patients by using inverse probability of treatment weighting based on estimated propensity score. Results: Among 648 very preterm infants at low risk of early-onset sepsis, 173 (26.2%) had early antibiotics treatment. Early antibiotic exposure was not associated with death or late-onset sepsis or necrotizing enterocolitis (OR=1.04 [95%CI=0.72-1.50]). However, it was associated with higher odds of severe cerebral lesions (OR=2.71 [95%CI=1.25-5.86]) and moderate-to-severe bronchopulmonary dysplasia (OR=2.30 [95%CI=1.21-4.38]). Conclusion: Early empirical antibiotics administrated in very preterm infants at low risk of early-onset sepsis were associated with a higher risk of severe cerebral lesions and moderate-to-severe bronchopulmonary dysplasia.