The role of tumour marker assays in differentiating malignant from benign pleural effusions is not yet clear. This study was designed to prospectively assess the individual and combined diagnostic utility of three tumour markers in patients with pleural effusion. Pleural and serum levels of carcinoembryonic antigen (CEA), carbohydrate antigen 15-3 (CA 15-3) and cytokeratin 19 fragment (CYFRA 21-1) were determined in 115 patients with pleural effusions (42 malignant and 73 benign). The diagnostic utility of each tumour marker was assessed using accuracy to determine the optimal cut-off point, whilst a logistic regression model was used to obtain the optimal combined test. In serum, every marker showed an individual high specificity (over 97%) for malignancy. The sensitivity of CEA, CA 15-3 and CYFRA 21-1 was 36, 48 and 31%, respectively. In patients without renal failure, the sensitivity of CYFRA 21-1 rose to 53%, while those of CEA and CA 15-3 remained almost unchanged. In pleural fluid, CYFRA 21-1 showed low sensitivity (32%) and specificity (82%), while CEA showed the highest sensitivity (57%). Excluding patients with renal failure, the combined determination in serum of CEA, CA 15-3 and CYFRA 21-1 has a high accuracy (88%), similar to that for CEA plus CA 15-3 in pleural fluid (87%). We conclude that CYFRA 21-1 is useless in pleural fluid and should not be used in serum for patients with renal failure. The combined determination of CEA, CA 15-3 and CYFRA 21-1 in serum may obviate its determination in pleural fluid.