Selective antegrade cerebral perfusion (SACP), which was adopted by many surgical groups for complex neonatal cardiac surgery, especially aortic arch repair, is a proven adjunct for neuroprotection during deep hypothermic circulatory arrest (DHCA). Several recent studies suggest that SUMO2/3 modification of proteins is markedly activated during deep hypothermia and believed to be an endogenous neuroprotective stress response. Here, we report that SACP reduces the increasing degree of SUMO2/3 conjugation following DHCA. Piglets were subjected to 1 h SACP and/or 1 h DHCA. DHCA was sufficient to markedly increase in protein SUMOylation by SUMO2/3 both in the hippocampus and cerebral cortex. SACP, especially at flow rate of 50 ml/kg/min, reduces the increasing degree of SUMO2/3 conjugation and also reduces levels of pro-apoptotic factors, Bax and Caspase 3, and increases levels of antiapoptotic factors, Bcl-2, following DHCA both in the hippocampus and cerebral cortex. This suggests that SACP at flow rate of 50 ml/kg/min is more appropriate for neuroprotection during DHCA in the pig model and level of protein SUMO2/3-ylation maybe an indicator of the degree of brain injury.