PurposeWe sought to determine the effect of acute severe hypoxia, with and without concurrent manipulation of carbon dioxide (CO2), on complex real-world psychomotor task performance.MethodsTwenty-one participants completed a 10-min simulated driving task while breathing room air (normoxia) or hypoxic air (PETO2= 45 mmHg) under poikilocapnic, isocapnic, and hypercapnic conditions (PETCO2= not manipulated, clamped at baseline, and clamped at baseline + 10 mmHg, respectively). Driving performance was assessed using a fixed-base motor vehicle simulator. Oxygenation in the frontal cortex was measured using functional near-infrared spectroscopy.ResultsSpeed limit exceedances were greater during the poikilocapnic than normoxic, hypercapnic, and isocapnic conditions (mean exceedances: 8, 4, 5, and 7, respectively; allp≤ 0.05 vs poikilocapnic hypoxia). Vehicle speed was greater in the poikilocapnic than normoxic and hypercapnic conditions (mean difference: 0.35 km h−1and 0.67 km h−1, respectively). All hypoxic conditions similarly decreased cerebral oxyhaemoglobin and increased deoxyhaemoglobin, compared to normoxic baseline, while total hemoglobin remained unchanged.ConclusionsThese findings demonstrate that supplemental CO2can confer a neuroprotective effect by offsetting impairments in complex psychomotor task performance evoked by severe poikilocapnic hypoxia; however, differences in performance are unlikely to be linked to measurable differences in cerebral oxygenation.Supplementary InformationThe online version contains supplementary material available at 10.1007/s00421-023-05151-1.