Cardiac myxoma is the most common primary tumor of the heart. The existence of apoptosis in cardiac myxoma has been demonstrated. The purpose of this investigation was to elucidate the pathway of apoptosis and the cell cycle in cardiac myxomas. This study had 2 parts: investigation of a cultured cardiac myxoma cell line and the analysis of data from 20 patients with cardiac myxoma that was surgically excised. Apoptosis signal transduction was determined by assessing DNA fragmentation, Fas ligand (FasL), Fas, tumor necrosis factor-α (TNF-α), caspase-3, and terminal deoxynucleotidyl transferase nick-end labeling (TUNEL) assay through immunohistochemical stain, quantitative reverse transcriptase- polymerase chain reaction (RT-PCR), and Western blot analysis. The patient population consisted of 12 (60%) women and 8 (40%) men with a mean age of 46 years (range = 32-64 years). All cases of myxoma were sporadic myxomas rather than familial. Clinical presentations included asymptomatic (26%), dyspnea (44%), stroke (9%), chest pain (9%), and fever (11%). All myxomas were located in the left atrium. Pathological scores for inflammation, cellularity, calcification, and thrombosis were not related to myxoma location or clinical events. In cardiac myxoma, apoptosis documented by TUNEL (70.9% ± 17.6%) and the caspase-3 (66.5% ± 32.5%) final common pathway is characterized by the extrinsic Fas/ FasL dependent pathway (positive stained 70.9% ± 19.2%; 26.0% ± 17.2%, respectively), but not the intrinsic pathway. The RT-PCR and Western Blot analysis (Fas/FasL, TNF-α, caspase-3, and apoptosis) of the cardiac myxoma and cultured cardiac myxoma cells confirmed the immunochemical results. The extrinsic Fas/FasL-dependent apoptosis pathways in cardiac myxomas were proved by both RNA and protein levels.