The determinants of hypoxemia were studied in 10 patients with acute pulmonary embolism demonstrated by pulmonary angiography. Two patients were mechanically ventilated, and in the 8 who breathed room air spontaneously, the mean arterial PO2 was 61.5 mmHg. Measurements of the distributions of ventilation (VA) and perfusion (Q) against VA/Q ratios by the multiple inert gas infusion technique demonstrated an increase in VA/Q inequality. The major part of pulmonary blood flow was distributed in a mode near to, or slightly above, a VA/Q ratio of 1. The cumulative fraction of blood in true shunt and low VA/Q mode (VA/Q less than 0.01) was 9.1%. For a small part of the AaDO2 (13%), an oxygen diffusional component was found. The remaining hypoxemia was due to the fall in the mixed venous PO2 (PVO2), irrespective of its cause: low cardiac output, low hemoglobin concentration, high oxygen consumption, low P50. The fall in PVO2 led to a fall in end-capillary blood PO2 in both shunt or ventilated and perfused units. We conclude that the major determinant of hypoxemia in these patients suffering from acute pulmonary embolism is the fall in PVO2. This is enhanced by a moderate increase in the fraction of blood flowing through low VA/Q units. Diffusion impairment plays only a minor role.