We examined subclinical alterations of cerebral function during carotid endarterectomy (CEA) and predictability of minor cerebral damage by perioperative levels of biochemical markers of brain damage (S100B and neuron-specific enolase [NSE]). Twenty consecutive patients with ≥70% asymptomatic carotid stenosis undergoing elective CEA were enrolled. Pre- and postoperative testing included magnetic resonance imaging (MRI) of the head, a standardized neurological exam, a battery of neuropsychological tests, and measurement of serum levels of S100B and NSE. There were no major ischemic strokes. In one patient, a mild weakness of the contralateral lower extremity was discovered on neurological examination; in another individual, postoperative MRI revealed two new small subcortical lesions without clinical correlate. While S100B increased significantly early after opening of the carotid clamp (p = 0.015), the NSE increase did not reach statistical significance. As a group, participants obtained a significantly higher mean overall neuropsychological score at follow-up testing (p < 0.05). In one patient, a significant decline of cognitive function was observed. This was the only individual to obtain a consistently high S100B and NSE increase. Neuropsychological testing combined with measurements of S100B and NSE may improve sensitivity when assessing subtle cerebral damage following CEA.