Asymmetric septal hypertrophy, or ASH, is a genetically determined myocardial disorder that is transmitted as an autosomal dominant trait. ASH is characterized by a disproportionately thickened ventricular septum that contains numerous hypertrophied, bizarrely-shaped and disorganized cardiac muscle cells. Disproportionate hypertrophy of the ventricular septum has also been observed in association with certain congenital cardiac malformations. To determine whether such congenital cardiac malformations are part of the disease spectrum of genetically determined ASH, cardiac pathologic observations were made in eight patients with disproportionate septal thickening (ventricular septal to posterobasal left ventricular free wall thickness ratios of 1.5 to 2.5) and the following three categories of associated lesions: 1) parachute deformity of the mitral valve (occurring either as an isolated lesion or with ventricular septal defect, coarctation of the aorta, supravalvular ring of the left atrium, or double outlet right ventricle); 2) complete interruption of the aortic arch; and 3) ventricular septal defect. The arrangement of cardiac muscle cells in the disproportionately thickened ventricular septum was normal in six of the eight patients; in the other two patients (one with parachute deformity of the mitral valve and one with ventricular septal defect) numerous bundles of hypertrophied cardiac muscle cells were interlaced in a disorganized fashion among more normally arranged bundles of cells. First degree relatives of six of the eight patients were studied by echocardiography and found to have normal ventricular wall thicknesses and septal-free wall ratios. It is concluded that disproportionate ventricular septal thickening may occur in patients with a variety of congenital heart malformations, but that such a finding is not necessarily a manifestation of the disease spectrum of genetically determined ASH.