Delirium following surgery is common and is associated with negative outcomes. Across surgical populations pre-operative cognitive impairment is a consistent risk factor for post-operative delirium. This study tests the hypothesis that the quantification of brain vulnerability, using neuropsychological tests, plasma and cerebrospinal fluid (CSF) biomarkers, and Apolipoprotein E status, can quantify the risk of post-operative delirium following elective primary arthroplasty surgery. An observational cohort study of patients over 65 years of age, admitted for elective primary hip or knee arthroplasty, under spinal anaesthetic, was undertaken with participants recruited between 23rd March 2012 and 21st October 2014. Of the 315 participants completing the study 40 (12.7%) developed delirium post-operatively. On univariate analyses several baseline characteristics, pre-operative performance on several neurocognitive tests, pre-operative plasma albumin concentration and CSF matrix metalloproteinase (MMP) 3 concentration were associated with post-oper:ative delirium. Only one pre-operative neuropsychological test - 3-item recall - and CSF MMP-3 concentration remained significant following multivariate analyses involving the entire cohort. The findings of this study support the hypothesis that quantification of brain vulnerability can predict the risk of delirium following elective arthroplasty surgery.