Four hundred fifteen patients with interventricular septal defect, proved at cardiac catheterization, have been followed for 1,407 patient years. As a group, they demonstrated marked growth failure in early childhood, which was more striking for weight than height. Ninety patients had serial hemodynamic studies without intervening cardiovascular surgery. Eight demonstrated spontaneous functional closure of their defect; only one progressed to the Eisenmenger syndrome. No patient with initially normal pressure developed pulmonary hypertension. Patients with initial pulmonary hypertension more commonly demonstrated regression than progression of the hypertension. Six patients developed bacterial endocarditis; all recovered. There was a frequent association (11 per cent) between interventricular septal defect and right ventricular outflow obstruction. Some patients developed increasing right ventricular outflow obstruction during the study. Eighteen patients with predominant right-to-left shunt were studied. Seventeen were cyanotic at the time of the initial study. The incidence of cyanosis was equal in the two sexes but females developed it later in life than males.Twenty-nine patients have died. Twenty-two deaths resulted from operative procedures; seven from the natural course of the disease. The principal factors associated with operative mortality was the presence of pulmonary hypertension and surgical repair before age 5. There were no operative deaths in patients with pulmonary artery systolic pressure below 65 mm. Hg. One patient died of progressive pulmonary hypertension 6 years after successful surgical closure of his defect.There is a great need for more information concerning the natural course of this disease in all age groups, both in the unoperated patient and in patients whose defects have been surgically closed.