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Contrast two-dimensional echocardiography (2DE) was used to demonstrate right-to-left shunting at the atrial level in a 49-year-old man with platypnea and orthostatic cyanosis which developed after a left pneumonectomy. This patient's systemic arterial saturation decreased with phlebotomy and increased with volume administration. This syndrome disappeared after repair of a previously unrecognized atrial septal defect. Right-to-left shunting in atrial septal defect is usually explained by a change in the relationship of right and left ventricular compliance with the right ventricle becoming less compliant (ie, stiffer) than the left. Pneumonectomy can affect atrial emptying either directly by mechanical means or indirectly by changing relationships in ventricular compliance. Contrast 2DE played a key role in initially establishing the etiology of cyanosis in this complicated case.