We present a case of synchronous breast and colon carcinoma in a pleural effusion, to our knowledge the first such reported case in the English-language literature. The patient was a 55-yr-old white female with known metastatic breast and colon carcinoma who developed a malignant pleural effusion which demonstrated two strikingly different populations of malignant cells by immunohistochemical study of cell block material. One cell population demonstrated a cytokeratin (CK)7+/CK20-/ER+ phenotype, while the other demonstrated a CK7-/CK20+/ER- phenotype, consistent with breast and colon origin, respectively. An immunohistochemical survey of archival breast and colon primary and metastatic carcinomas confirmed the established CK7+/CK20- phenotype of breast and CK7-/CK20+ phenotype of colon primary carcinomas, and the maintenance of this phenotype in metastases thereof. A survey of benign and malignant mesothelial lesions confirmed the absence of staining for estrogen receptor, but showed 6/10 cases weakly positive for CK20, which has not been described in other published series. This unusual case graphically illustrates the utility of cytokeratin subset immunohistochemistry in effusion cytology.