The cause of pleural effusion in 108 of 133 patients was determined by laboratory tests and clinical examination; it was indeterminate in 25, even after complete diagnostic evaluation. In 164 diagnostic thoracenteses, 136 cytologic examinations were done; the results were positive for cancer in 20 (15%). Five of 19 patients (26%) with bronchogenic cancer, 13 of 25 (52%) with metastatic cancer of the lung, and two of 20 (10%) with lymphoma had positive results on cytologic examination. Of 143 routine bacterial cultures, only five were positive (3%). Of 103 mycobacterial and 76 fungal cultures, only one was positive in each instance. Despite the high incidence of indeterminate diagnoses, we recommend that only measurement of protein content and cytologic examination be ordered routinely. Our algorithm provides a logical, cost-effective approach to the diagnostic problem of pleural effusion.