To evaluate the association of antenatal corticosteroids (ACS) therapy on the risk for cystic periventricular leukomalacia (c-PVL) in very low birth weight (VLBW), very preterm infants, whilst accounting for the occurrence of major neonatal morbidities; sepsis, necrotising enterocolitis, intraventricular haemorrhage and bronchopulmonary dysplasia. Population-based observational cohort study applying data collected by the Israel national VLBW infant database from 1995-2016. Cystic PVL was diagnosed in 692 (6.8%) of the 10,170 study infants. Among 7522 infants exposed to ACS, the rate of c-PVL was 5.4%, compared to 10.7% among those not exposed (p < 0.0001). ACS was associated with significantly lower odds for c-PVL (Odds Ratio [OR] 0.69, 95% confidence interval [CI] 0.57-0.84). In subgroup analyses, excluding infants with one or more morbidities the rates of c-PVL ranged from 2.7% to 5.4% among infants exposed to ACS compared to 5.6% to 10.7% in those not exposed (all p < 0.0001). ACS was associated with significantly lower OR's for c-PVL in all subgroups, ranging from 0.52 (95% CI 0.40-0.66) to 0.62 (95% CI 0.50-0.77). Infants exposed to ACS had a significantly lower risk of c-PVL. Subgroup analyses excluding infants with major neonatal comorbidities showed a consistent reduction of 40%-50% in the risk for c-PVL following ACS therapy. ©2021 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.