Aim: Carotid endarterectomy is a widely accepted procedure for stroke prevention, and carotid clamping is a necessary surgical step. Glutathionylated haemoglobin (HbSSG) has been recently employed as a biomarker of oxidative stress, its level being increased under several conditions, including hypoxia. This study aims to evaluating whether HbSSG level in peripheral and/or jugular blood is affected during carotid surgery under normal routine operative conditions. Methods: This study enrolled 13 consecutive patients undergoing elective carotid endarterectomy under general anesthesia. At different times during surgery, blood was taken simultaneously from both a peripheral vein and the jugular vein ipsilateral to the clamped carotid. HbSSG was measured in RBC hemolysates by MALDI-ToF mass spectrometry in each sample. Results: Three patients showed a complex pattern of rise and fall of HbSSG levels in different time periods before, during and after surgery. They also showed statistically significant differences between peripheral and jugular blood, with mean HbSSG levels in jugular blood higher by approx. 30% than those of peripheral blood at the end of the period of carotid clamping. In all three patients HbSSG levels fell to pre-clamping values within 2 min from removal of carotid artery clamp. Conclusion: Although effective routine drug management allowed brain safety during carotid clamping time, a number of patients showed a fast modification over time of the HbSSG levels in jugular blood, suggesting that "resident" cerebral biochemical protection mechanisms could play some role to compensate clinically silent brain oxidative stress.