To determine the clinical features, course and outcome of patients with cardiac tamponade, 57 consecutive patients with new, large pericardial effusions were prospectively studied. Twenty-five patients (44%) developed cardiac tamponade with venous hypertension and a pulsus paradoxus greater than 10 mm Hg. Electrocardiography, radiographic studies and echocardiography did not differentiate patients with and without tamponade. All 57 patients underwent thorough diagnostic evaluation followed by subxiphoid pericardial biopsy and drainage. A diagnosis was obtained in 53 patients (93%). Collagen vascular disease was significantly more frequent in the 25 patients with than in the 32 without cardiac tamponade (24 vs 3%; p less than 0.05). The frequency of malignant and uremic effusions was equal in both groups, whereas radiation-induced effusions seldom produced tamponade. At 1-year follow-up, 3 patients (12%) with tamponade had recurrent effusions, and 1 needed reoperation. This was not significantly different from the 32 patients without tamponade. Twelve-month mortality was also similar in both groups (36 vs 44%). This prospective series disclosed several unexpected findings: (1) Cardiac tamponade occurred in almost 50% of patients with new large pericardial effusions; (2) both malignancy and collagen vascular disease occurred with equal frequency as etiologies, whereas radiation-induced tamponade was unusual; (3) thorough clinical evaluation resulted in few idiopathic etiologies; and (4) subxiphoid pericardiotomy was effective for both diagnosis and therapy of tamponade.