The pathologic anatomic features and associated cardiac anomalies of 13 patients with aorticopulmonary septal defect (APSD) and of 236 previously reported cases were analyzed. Morphologically, 3 types of APSD were distinguished: a defect with a more or less circular border located about halfway between the arterial valves and the bifurcation of the pulmonary trunk; a similarly located defect in which the border represents a helix; and a usually large defect in which there is no posterior (distal) border. The appearance of these 3 types of defects suggests a different developmental mechanism for each. Approximately half of the cases of APSD are not associated with other cardiovascular anomalies. Of the anomalies that do occur, anomalous origin of a coronary artery from the pulmonary trunk and interruption of the aortic arch (IAA) type A or severe preductal coarctation are seen far more often than expected. An association with DiGeorge syndrome, frequently noted with persistent truncus arteriosus (TA) and IAA type B, was not seen. Certain cardiac anomalies often seen with TA are rarely seen with APSD, and defects often seen with APSD are rarely seen with TA. These observations indicate that APSD and TA are pathogenetically unrelated even though located in the same region of the heart and, unlike TA and IAA type B, APSD is probably not due to a developmental error involving the neural crest.