Two near-infrared spectroscopy (NIRS) devices were compared with regard to their responses to changes in cerebral hemoglobin oxygenation induced by hypoxia and hypercapnia in five healthy volunteers. Sensors belonging to each NIRS device were placed on opposite sides of the volunteer's forehead. The INVOS-3100A device, approved by the United States Food and Drug Administration, records the percentage of oxyhemoglobin (HbO2) saturation and the investigational NIRO500 device records absolute changes in HbO2, deoxyhemoglobin, and total hemoglobin in micromolar concentrations referenced to an arbitrary baseline. The volunteers breathed separate mixtures of 7% CO2 in O2 and 10% O2 for 5 minutes in random order. Arterial blood pressure, end-tidal CO2 (ETCO2), arterial O2 saturation, and electrocardiographic data were continuously monitored. Hypercapnia increased (p < 0.01) ETCO2 from 42+/-2 to 56+/-3 mm Hg (mean +/- standard deviation), resulting in a 7.3+/-0.2% increase (p < 0.005) in cerebral HbO2 saturation detected by the INVOS3100A device and an 11.6+/-3 microM increase (p < 0.0008) in HbO2 detected by the NIRO500. Hypoxia decreased (p < 0.01) arterial HbO2 saturation from 98+/-1 to 87+/-3%, causing a 5.1+/-1.2% decrease (p < 0.01) in the percentage of HbO2 saturation detected by the INVOS3100A device and a 9.7+/-6.3 microM decrease in HbO2 detected by the NIRO500. The responses of the NIRO500 and the INVOS3100A instruments to changes in cerebral oxygenation resulting from hypercapnia and hypoxia were generally similar; however, responses tended to be greater when recorded by the NIRO500 device, perhaps because, unlike the INVOS3100A device, the NIRO500 does not correct for skin and bone contamination.