BACKGROUND: The cause of pericardial disease often is unclear. Pericardial surgery provides a unique opportunity to obtain tissue and fluid samples for diagnostic tests. We report our experience with these tests and assess their value in etiologic determination. STUDY DESIGN: The medical records of 92 who underwent 95 operations for pericardial disease were reviewed. The procedures included 75 biopsies and drainages and 20 pericardiectomies. We analyzed the diagnostic yields of routine histology of the removed pericardial specimens, together with culture, cytology, and biochemistry examinations of the fluid drained. RESULTS: A specific etiologic diagnosis was obtained in 20 patients (22 percent): 12 neoplasias, 5 infections (1 bacterial, 4 tuberculoses), 2 chylopericardia, and 1 amyloidosis. Diagnosis was made histologically in 10 (10.5 percent) of 95 examinations, cytologically in 12 (16 percent) of 73 examinations, by culture in 5 (7 percent) of 73 examinations, and by biochemistry in 2 (3 percent) of 73 examinations. Pericardial disease was the first manifestation of an underlying extrapericardial disorder in 11 patients (12 percent), and 8 of these patients had neoplasias and 3 had tuberculoses. Twenty-seven patients (29 percent) had underlying neoplastic disease, and in 15 patients, neither cytology nor histology revealed neoplastic involvement of the pericardium. In 2 of the 15 patients, who died shortly after the operation, pericardial invasion was demonstrated at postmortem examination. CONCLUSIONS: One fifth of the patients had a specific etiologic diagnosis with important implications for prognosis and management, supporting the routine use of diagnostic tests in all pericardial surgical procedures. Negative cytology and histology results do not rule out pericardial invasion in patients with neoplastic disease.