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Epithelial malignancies frequently metastasize to the serous cavities and result in symptomatic effusions. Cytology has high specificity but moderate sensitivity for the diagnosis of a malignant effusion. We developed and validated a simple, rapid, 3-color flow cytometric panel using the adhesion molecule Ber-EP4 to detect epithelial cells in effusions. One hundred ninety-five consecutive benign and malignant effusions received for routine cytologic examination were analyzed. Eighty-three fluid specimens were benign and 76 were malignant as judged by follow-up data. Ber-EP4–positive cells were detected with flow cytometry in 89.3% of malignant effusions. The sensitivity and specificity of flow cytometry was 88.15% and 97.64% compared with 73.68% and 100% on cytologic examination alone for the presence of a malignant effusion. Flow cytometry is a useful adjunct to cytology for the diagnosis of a malignant effusion and is particularly useful if the cytologic diagnosis is atypical/suspicious or if the cytologic preparations are hypocellular or hemorrhagic.