BACKGROUND We hypothesized, after seeing several suggestive clinical examples, that a process leading to a large bilateral pleural effusion in the presence of an otherwise insignificant pericardial effusion could result in right ventricular diastolic collapse (RVDC) as seen by two-dimensional echocardiography. This noninvasive marker for hemodynamically significant cardiac tamponade occurs when pericardial fluid is under pressure. Therefore, RVDC resulting from a large pleural effusion would represent a false-positive indication of cardiac tamponade caused by excessive pericardial fluid. RESULTS Seven spontaneously breathing dogs were chronically instrumented to measure ascending aortic, right atrial, intrapericardial, intrapleural, left atrial, and pulmonary artery pressures and cardiac output. Intravascular volume was adjusted before each experiment to the euvolemic range with saline solution. The onset of RVDC was observed in each animal by two-dimensional echocardiography during seven paired episodes of tamponade induced by infusions of warm saline into the pericardial space alone and, after drainage of the pericardial fluid and complete recovery, into the pleural space in the presence of a small pericardial effusion. The onset of RVDC occurred at the same intrapericardial (8.17 versus 9.47 mm Hg) and right atrial (7.41 versus 7.46 mm Hg) blood pressures regardless of whether it was produced by an intrapericardial or an intrapleural effusion but began in expiration during the former and in inspiration during the latter. Intrapericardial pressure increased in the same manner as intrapleural pressure during intrapleural saline infusion. Nevertheless, cardiac output and aortic blood pressure were better preserved, and at the onset of RVDC, the pulmonary artery systolic blood pressure was higher (p less than 0.0001) and the degree of pulsus paradoxus lower (p less than 0.01) with intrapleural infusion. CONCLUSIONS These results indicate that a large bilateral pleural effusion can elevate intrapericardial pressure sufficiently to cause RVDC and, perhaps, lead to misdirected therapy of an otherwise insignificant pericardial effusion.