Background/Aims: Post-operative cognitive decline is frequent in older individuals following major surgery; however, biomarkers of this decline are less clearly defined. Methods: Sixty-eight participants over the age of 60 provided blood samples at baseline and 24 h post-surgery. Cognitive decline was measured at baseline and 52 weeks post-surgery using the Cambridge Assessment for Mental Disorder in the Elderly, section B (CAMCOG) score. Plasma levels of neuron-specific enolase (NSE) and S100B were measured by ELISA. Results: Baseline NSE and the change in NSE levels between baseline and 24 h were correlated with the change in CAMCOG score between baseline and 52 weeks. Conclusion: NSE concentrations may be a useful predictor of individuals at risk of more severe long-term cognitive decline