To investigate whether pleural levels of the soluble oncoprotein 185 HER-2 (sp185 HER-2 ), individually or in combination with CEA and CA 15-3, were useful for the diagnosis of malignant effusions.Levels of CEA, CA 15-3, and sp185 HER-2 were measured in the pleural fluid from 135 malignant and 103 benign effusions. Thresholds of these tumor markers were chosen for a diagnostic specificity of ≥99%.Pleural sp185 HER-2 levels greater than 25 ng/mL were observed in 20% of breast and 10% of lung adenocarcinomas, and predicted a malignant effusion with a sensitivity of 7% and a likelihood ratio of 7.6. Combination of CEA and CA 15-3 resulted in 50% sensitivity, while adding sp185 HER-2 to this panel nonsignificantly increased sensitivity by 5% (P = 0.45). Only 1 patient with breast adenocarcinoma among 45 cytology-negative malignant effusions had sp185 HER-2 above the diagnostic cutoff point.Measurement of pleural fluid sp185 HER-2 has poor diagnostic performance in patients with malignant effusions.