The alveolar-arterial oxygen tension difference provides a useful clinical indication of ventilation-blood flow mismatching in the lungs. In some clinical situations involving alveolar hypoxia (e.g., patients with chronic obstructive lung disease flying in commercial aircraft or normal humans at high altitudes) it would be useful to know this tension difference to predict the likely arterial PO2 under such potentially stressful conditions. Such estimates would require multiple arterial punctures performed under a variety of trying circumstances, conditions usually far distant from a suitable analytic facility. Consequently, we induced controlled hypoxia in 23 healthy humans and calculated changes in the alveolar-arterial oxygen tension difference during the hypoxic challenge test. We plotted this difference as a function of the alveolar oxygen tension over a range from 35 to 110 mm Hg. In addition to a series of control studies in which multiple arterial blood samples were obtained, we calculated arterial PO2 by converting the arterial oxyhemoglobin saturation (measured with an ear oximeter) into partial pressure of oxygen. During hypoxic procedures in which levels of oxygenation fell on the steep section of the oxyhemoglobin dissociation curve, fixing PCO2 at constant predetermined levels allowed accurate predictions of arterial PO2. We were able to demonstrate that the alveolar-arterial oxygen tension difference narrowed with decreasing alveolar oxygen tension, and that measurement with an ear oximeter provided data that allowed a reasonable estimate of the tension difference during hypoxic conditions.