Background: Postoperative cognitive dysfunction (POCD) occurs commonly after cardiac surgery. Near-infrared spectroscopy (NIRS) has been used to monitor regional cerebral oxygen saturation (rScO₂) in order to minimise the occurrence of POCD by applying dedicated interventions when rScO₂ decreases. However, the association between rScO₂ intraoperatively and POCD has not been clarified. Methods: This is a secondary analysis of a randomised trial with physician-blinded NIRS monitoring and cognitive testing at discharge from hospital and at 3 months after surgery. The association between intraoperative rScO₂ values and POCD at discharge from hospital and at 3 months after surgery was investigated. The prespecified candidate predictive variable of interest was cumulative time during surgery with rScO₂ ≥10% below its preoperative value. Results: One hundred and fifty-three patients had complete NIRS data and neurocognitive assessments at discharge, and 44 of these patients (29%) had POCD. At 3 months, 148 patients had complete data, and 12 (8%) of these patients had POCD. The median time with rScO₂ >10% below preoperative values did not differ for patients with and without POCD at discharge (difference=0.0 min; Hodges-Lehmann 95% confidence interval, −3.11–1.47, P=0.88). Other rScO₂ time thresholds that were assessed were also not significantly different between those with and without POCD at discharge. This applied both to absolute rScO₂ values and relative changes from preoperative values. Similar results were found in relation to POCD at 3 months. Conclusions: No significant association was found between intraoperative rScO₂ values and POCD. These findings bring into question the rationale for attempting to avoid decreases in rScO₂ if the goal is to prevent POCD. Clinical trial registration: NCT 02185885.