The oxygen tension in mixed venous blood (Pvo2) is often used in the critical care setting to evaluate cardiac output and tissue oxygenation. Because positive-pressure ventilation may affect tissue oxygenation by reducing cardiac output, Pvo2 may be relied on to guide respiratory care in the critically ill patient. This report describes a patient with deteriorating hemodynamic and pulmonary status in whom treatment included fluid therapy, vasopressors, and mechanical ventilation with positive end-expiratory pressure. A pulmonary artery catheter allowed serial measurements of Pvo2, which initially seemed to correspond well with the degree of tissue oxygenation. However, as tissue perfusion diminished, Pvo2 remained normal or supranormal in the presence of increasing tissue hypoxia. This patient's clinical course illustrates that, in some clinical situations, Pvo2 may be unreliable as an index of tissue oxygenation.