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Purpose: Animal studies have demonstrated that propofol post-conditioning produces long-term neuroprotection in focal cerebral ischemia-reperfusion injury. However, whether propofol post-conditioning provides neuroprotection in human beings has never been explored. The aim of this study was to evaluate the role of propofol post-conditioning on oxidative stress and post-operative cognitive function following aneurysm clipping. Materials and Methods: Sixty patients undergoing intracranial aneurysm clipping were randomized into a propofol post-conditioning group or a sevoflurane group. Sevoflurane (0.5-2%) was used for maintenance anesthesia in both groups. In the propofol post-conditioning group, the inhaled concentration of sevoflurane was reduced after temporary clip removal to keep the bispectral index (BIS) value between 40 and 60, and propofol (Cp 1.2 µg/mL) was subsequently started. Blood samples were drawn at six time points: before induction, immediately after clip removal, at the end of the operation, 24-h post-surgery, 3 days post-surgery, and 7 days post-surgery. Oxidative stress and cognitive function were measured. Results: Between the conclusion of the operation to 7 days after surgery, propofol post-conditioning decreased the serum concentration of •OH and 8-isoprostane and increased γ-tocopherol and SOD. Reduced micronuclei and nucleoplasmic bridges were observed in the propofol post-conditioning group. Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) scores were improved by propofol post-conditioning compared to the group that received no propofol. Conclusions: Together, our data suggest that propofol post-conditioning (Cp 1.2 µg/mL) may protect the brain from oxidative stress injury up to 7 days post-surgery after temporary parent artery clipping. Furthermore, the neuroprotection induced by propofol post-conditioning may contribute to improvement in cognitive function. [ABSTRACT FROM AUTHOR]