Various cardiovascular operations are performed during conditions of deep hypothermic circulatory arrest. Here we investigated the effects of deep hypothermia on the small ubiquitin-like modifier (SUMO) conjugation pathway using a clinically relevant animal model of deep hypothermic cardiopulmonary bypass (DHCPB). Deep hypothermic cardiopulmonary bypass induced a marked activation of the SUMO conjugation pathway and triggered a nuclear translocation of SUMO2/3-conjugated proteins. Furthermore, DHCBP significantly modified gene expression. Activation of the SUMO conjugation pathway is believed to protect neurons from damage caused by low blood flow. This pathway may, therefore, play a key role in defining the outcome of cells exposed to DHCPB.