The immunoreactivities of surgically removed 16 cardiac myxomas were studies for factor VIII-related Ag (F VIII-RA), Ulex europaeus agglutinin I (UEA-I) and desmin alpha1-antichymotrypsin, and this study was accompained by a clinicopathologic review. More than 50% of the patients with cardiac myxomas were in their fourth and fifth decades, and cardiac myxomas were much more common in women than in men. All but on occurred in the left atrium, and the majority were attached to the atrial septum, usually in the region corresponding to the fossa ovalis. In one case, an atrial myxoma recurred 37 months after the initial excision. Microscopically, the myxomas contained a myxoid matrix composed of acid mucopolysaccharides within which were embedded polygonal cells. The cells forming both the surface and complicated vascular like channels throuhout the myxoid stroma tested positive for F VIII-RA and UEA-I. The outer cell layers of the complex vascular structures demonstrated variable staining for F VIII-RA, while isolated bundles of smooth muscle cells were present and stained for desmin. A small number of the so-called myxoma cells, immunoreactive for alpha1-antichymotrypsin which were not laden with hemosiderin pigment but were similar to histiocytes, were present particularly around the areas of hemorrhage. These findings support the current view that cellular and histologic heterogeneity arose from the divergent differentiation of multipotential mesenchymal cells. In particular, it remains to be confirmed by further study whether or not true histiocytic differentiation occurs.