Morphologic features of spontaneously occurring hypertrophic cardiomyopathy (HC) were compared in 38 humans, 51 cats and 10 dogs. Asymmetric hypertrophy of the ventricular septum, marked disorganization of cardiac muscle cells, abnormal intramural coronary arteries and myocardial fibrosis were each present in the ventricular septum of human, feline, and canine forms of HC; these abnormalities were generally more severe and most frequently identified in humans. Asymmetric left ventricular hypertrophy (based on the calculated septal-to-free wall thickness ratio) was most common in humans (31 of 38 [81%]) and dogs (8 of 10 [80%]), as compared with cats (16 of 51 [31%]; p < 0.001) with HC; in all 3 species, hypertrophy was often diffuse, involving substantial portions of the anterolateral and posterior free walls, and the ventricular septum. Marked septal disorganization (> or = 5% of the tissue section) was present in 35 patients (92%), but in only 14 cats (27%) and 2 dogs (20%) (p < 0.001). Abnormal intramural coronary arteries occurred with similar frequency in the ventricular septum of patients (n = 25; 66%), cats (n = 38; 74%) and dogs (n = 6; 60%) (p < NS). Moderate-to-severe septal fibrosis was identified more commonly in humans (15 of 38 [39%]) than in animals (13 of 61 [21%]; p < 0.001). In all 3 species, abnormal intramural coronary arteries were most commonly observed within or at the margins of areas of fibrous tissue. These morphologic findings describe spontaneously occurring models of HC in cats and dogs with substantial structural similarities to the well-recognized disease entity in humans.