Hyperoxia during diving has been suggested to exacerbate hypercapnic narcosis and promote unconsciousness. We tested this hypothesis in male volunteers (12 at rest, 10 at 75 W cycle ergometer exercise) breathing each of four gases in a hyperbaric chamber. Inspired Po2 (PiO2 ) was 0.21 and 1.3 atmospheres (atm) without or with an individual subject's maximum tolerable inspired CO2 (PiO2 = 0.055-0.085 atm). Measurements included end-tidal CO2 partial pressure (PetCO2 ), rating of perceived discomfort (RPD), expired minute ventilation (V̇e), and cognitive function assessed by auditory n-back test. The most prominent finding was, irrespective of PetCO2 , that minute ventilation was 8-9 l/min greater for rest or exercise with a PiO2 of 1.3 atm compared with 0.21 atm (P < 0.0001). For hyperoxic gases, PetCO2 was consistently less than for normoxic gases (P < 0.01). For hyperoxic hypercapnic gases, n-back scores were higher than for normoxic gases (P < 0.01), and RPD was lower for exercise but not rest (P < 0.02). Subjects completed 66 hyperoxic hypercapnic trials without incident, but five stopped prematurely because of serious symptoms (tunnel vision, vision loss, dizziness, panic, exhaustion, or near syncope) during 69 normoxic hypercapnic trials (P = 0.0582). Serious symptoms during hypercapnic trials occurred only during normoxia. We conclude serious symptoms with hyperoxic hypercapnia were absent because of decreased PetCO2 consequent to increased ventilation.