BACKGROUND: Many cases of cardiac masses have been reported in the literature, but in this case report we described a rare case of biatrial cardiac mass that represented a challenge for diagnosis and therapy. The differentiation between cardiac masses such as thrombi, vegetations, myxomas and other tumors is not always straightforward and an exact diagnosis is important because of its distinct treatment strategy. Transthoracic/esophageal echocardiography and cardiac magnetic resonance play an important role in establishing the diagnosis of cardiac masses. However, no current noninvasive diagnostic tool has the ability to absolutely diagnose cardiac masses; obtaining a pathological specimen by surgical resection of cardiac masses is the only reliable method to diagnose cardiac masses accurately. Our case report is an exception in that the final diagnosis was affirmed by empirical anticoagulation therapy based on clinical judgment and noninvasive characterization of biatrial mass. CASE PRESENTATION: We described a 54-year-old Malay man with severe mitral stenosis and atrial fibrillation who presented with a biatrial mass. Transthoracic/esophageal echocardiography and cardiac magnetic resonance detected a large, homogeneous right atrial mass typical of a thrombus, and a left atrial mass adhering to interatrial septum that mimicked atrial myxoma. The risk factors, morphology, location, and characteristics of the biatrial cardiac mass indicated a diagnosis of thrombi. However, our patient declined surgery. As a result, the nature of his cardiac masses was not specified by histology. Of note, his left atrial mass was completely regressed by long-term warfarin, leaving a residual right atrial mass. Thus, we affirmed the most probable diagnosis of cardiac thrombi. During the course of treatment, he had an episode of non-fatal ischemic stroke most probably because of a thromboembolism. CONCLUSIONS: Noninvasive characterization of cardiac mass is essential in clarifying the diagnosis and directing treatment strategy. Anticoagulation is a feasible treatment when the clinical assessment, risk factors, and imaging findings indicate a diagnosis of thrombi. After prolonged anticoagulation therapy, complete resolution of biatrial thrombi was achievable in our case.