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Background and Aims: Infants exposed to major surgery are at risk of injuries to the immature brain because of reduced arterial oxygen saturation. This study compared the effect of volume-controlled ventilation (VCV) versus pressure-controlled ventilation (PCV) on cerebral oxygenation in neonates subjected to repair of tracheoesophageal fistula (TEF) under video-assisted thoracoscopic surgery (VATS). Methods: This randomised controlled study included 30 full-term neonates scheduled for VATS for managing TEF under general anaesthesia. They were randomised to either VC group (n = 15), who received VCV, or PC group (n = 15), who received PCV. Cerebral oxygenation (rScO2) was monitored throughout the surgery with documentation of episodes of cerebral desaturation. Peripheral oxygen saturation, partial pressure of carbon dioxide (PaCO2), and end-tidal carbon dioxide were recorded at baseline, after induction of anaesthesia, and every 30 min till the end of the surgery. Results: rScO2 was significantly higher in the PC group than the VC group at baseline and was significantly higher in the VC group after 15 min (P = 0.041). Later, it was comparable in both the groups up to 60 min after starting the surgery. Cerebral desaturation was significantly more common in the PC group (80%) compared to VC group (33.3%) (P = 0.010). PC group required higher fraction of inspired oxygen and positive end-expiratory pressure to prevent cerebral desaturation. PaCO2 was significantly higher in the PC group than the VC group at 30 and 60 min (P = 0.005 and 0.029). Conclusion: VCV is safer than PCV for cerebral oxygenation during VATS in neonates. [ABSTRACT FROM AUTHOR]