A review is presented of the clinical and cardiac morphologic findings in 50 previously reported and 3 new patients with histiocytoid cardiomyopathy. This disorder occurs in infants and small children and is characterized clinically by severe and often fatal arrhythmias and morphologically by focal collections of altered myocytes that are roundshaped and resemble histiocytes. Sixteen patients had yellowish nodules on the endocardium, epicardium, and/or valves; the other 37 had foci of abnormal myocytes throughout the myocardium. These cells were remarkably similar in all patients and had poorly developed or absent intercellular junctions, few or no contractile elements, and markedly increased numbers of mitochondria, which imparted a granular or vacuolated appearance to the cytoplasm. There was a high prevalence of anomalies involving the nervous system and eyes and of oncocytic cells in various glands. Evidence is presented to exclude the possibilities that the disorder represents a developmental anomaly of the atrioventricular conduction system, a multifocal tumor of Purkinje cells, a developmental arrest of cardiac myocytes, and a diffuse type of mitochondrial cardiomyopathy. Histiocytoid cardiomyopathy is considered to be the result of hamartoma-like aggregations of cardiac myocytes with features similar to those of oncocytes. This syndrome is likely caused by prenatal myocardial or systemic (viral?) injury. Surgical excision of nodules of histiocytoid cells can result in clinical remission.