Because of current limitations in improving metabolic support to the brain during hypothermic circulatory arrest (HCA), attenuation of ischemia-reperfusion injury remains an area of therapeutic intervention of relevance. Apotransferrin (Apo-Tf), alpha 1-acid glycoprotein (AGP), and C1-esterase inhibitor (C1-INH) have been herein evaluated as potential beneficial agents in reducing the ischemia-reperfusion injury in a surviving model of HCA.Apo-Tf 100 mg/kg (n = 6), C1-INH 50 IU/kg (n = 6), AGP 100 mg/kg (n = 6), or NaCl 0.9% 2 ml/kg (n = 6) were randomly administered to 24 juvenile pigs after a 75-min period HCA at a brain temperature of 18 degrees C.Animals in the Apo-Tf group had a slightly better 7-day survival (66.7%) compared with the other study groups (50%), but such a difference was not statistically significant. Some favorable changes in the brain glucose metabolism parameters were observed in the AGP, C1-INH, and Apo-Tf groups, but these did not reach statistical significance. Semiquantitative analysis of the histopathological findings did not show any significant difference between the study groups. However, only two out of four surviving animals in the Apo-Tf group developed brain infarction, whereas all three survivors of the remaining study groups developed brain infarction.Although the small size of the study groups may affect the present findings, none of the metabolic and hemodynamic parameters as well as outcome endpoints indicate a substantial therapeutic efficacy of Apo-Tf, AGP, and C1-INH as neuroprotective agents after experimental HCA.