Large pleural effusions are typically associated with dyspnea and potential respiratory compromise. Experimental evidence suggests that with large effusions, increased intrapleural pressure may be transmitted to the pericardial space, resulting in impaired cardiac filling and reduced stroke volume. We report two cases in which large pleural collections were complicated by hypotension. The effusions were due to an infected right hepatic hydrothorax (Case 1) and a left malignant effusion (Case 2). Echocardiography demonstrated right and left ventricular diastolic collapse, respectively, confirming a diagnosis of cardiac tamponade. Large volume thoracentesis resulted in immediate hemodynamic improvement as demonstrated by a reduction in right ventricular and atrial pressures (Case 1) and echocardiographic resolution of left ventricular diastolic collapse (Case 2). These cases establish that large pleural effusions can cause hemodynamically significant cardiac tamponade. In addition, they illustrate how the demonstration of cardiac compressive physiology can significantly alter the therapeutic approach to large pleural effusions.