Despite careful clinical, noninvasive, and hemodynamic assessment of patients with constrictive/restrictive physiology, the differentiation of restrictive cardiomyopathy from constrictive pericarditis remains difficult. We examined the role of right ventricular endomyocardial biopsy in defining the underlying process in 54 patients with evidence of constrictive/restrictive physiology, including 38 patients with profound symptoms of heart failure in whom diagnostic/therapeutic thoracotomy was contemplated (group I) and 16 patients with milder symptoms (group II). All patients in group I had NYHA class III or IV heart failure with depressed cardiac index (mean 2.5 liters/min/m2), right atrial hypertension (mean 15 mm Hg), and normal left ventricular ejection fraction (mean 59%). Endomyocardial biopsy identified a specific source of restrictive cardiomyopathy in 15 of 38 patients (39%) (11 amyloid, four myocarditis). Of the 23 remaining patients with either normal biopsy findings or nonspecific abnormalities on biopsy, 18 had intraoperative or autopsy evaluation of their pericardium, and constriction was found in 14 (77%). A specific form of restrictive cardiomyopathy was also identified in four of the 16 patients with milder symptoms (group II). We conclude that endomyocardial biopsy is useful in patients with severe constrictive/restrictive physiology. It identifies a large subset of patients with specific forms of restrictive cardiomyopathy in whom thoracotomy should be avoided. It supports the need for thoracotomy and the likelihood of finding pericardial constriction in patients without specific pathologic findings.