STUDY OBJECTIVE To determine the associations between postoperative cognitive dysfunction (POCD) and plasma concentrations of stable nitric oxide products [nitric oxide index (NOi)]. DESIGN Prospective study. SETTING Academic hospital. PATIENTS 28 ASA physical status I, II, and III physical status patients undergoing major non-cardiac surgery. INTERVENTIONS Cognitive assessment was performed preoperatively and postoperatively at 4 days (early) and 6 weeks (late). MEASUREMENTS Serial measurements of plasma NOi were recorded. MAIN RESULTS Early POCD with a deficit in one cognitive domain was present in 18 patients (64%), and in 8 patients (28%) with deficits in two or more cognitive domains. Late POCD was evident in three patients (20%) who had a deficit in one domain. Eight patients were lost to late follow-up. There was no difference in baseline or subsequent serum concentrations of NOi between those who showed early and late POCD and those who showed no POCD. CONCLUSION Factors other than nitric oxide-mediated injury is responsible for POCD following major non-cardiac surgery.