The distinction between reactive mesothelial cells and carcinoma in pleural, peritoneal, and pericardial fluids is often difficult. We and others previously showed that E‐cadherin, an epithelial‐specific adhesion protein, can be useful for this distinction. In this study we tested the sensitivity and specificity of E‐cadherin compared to, and in combination with, conventional cytology for assessment of carcinoma in fluids. Cytyc ThinPrep™ slides (Marlborough, MA) from 102 sequential fluids were evaluated for E‐cadherin expression by routine immunologic techniques. No evidence of E‐cadherin staining was seen in 71 cases, while 31 showed unequivocally positive staining. Sensitivity and specificity were independently determined for E‐cadherin alone (72% and 97%, respectively), cytomorphology alone (62% and 100%, respectively), and both together (92% and 100%, respectively). We conclude that assessment of E‐cadherin expression has sensitivity and specificity comparable to, or better than, conventional cytomorphology. If both cytomorphology and E‐cadherin are used together, a definitive and correct diagnosis could have been made on nearly every case in this study. Diagn. Cytopathol. 2000;22:263–267. © 2000 Wiley‐Liss, Inc.