To evaluate the use of a panel of markers to differentiate adenocarcinoma and the reactive/inflammatory process in fluid cytology, we stained 29 formalin-fixed, paraffin-embedded cell blocks of effusion fluid from patients with metastatic adenocarcinoma and 24 cell blocks from patients with benign effusion with mucicarmine and antibodies to carcinoembryonic antigen (CEA), B72.3, and calretinin. Positive staining with CEA, B72.3, and mucicarmine was seen in 22 (76%), 20 (69%), and 18 (62%) adenocarcinoma cases, respectively. All except 1 adenocarcinoma was negative for calretinin. No benign cases were positive for B72.3 and mucicarmine. In 1 benign case, scattered epithelial cells demonstrated weak positivity for CEA. The majority of combinations were 100% specific for adenocarcinoma. The highest sensitivity (86%) for adenocarcinomas was achieved with the staining combination of negative for calretinin and positive for any adenocarcinoma marker (CEA, B72.3, or mucicarmine). The use of a panel of markers that recognize adenocarcinoma and mesothelial cells is useful in the differential diagnosis between metastatic adenocarcinoma and the reactive/inflammatory process. The profile of positive staining with at least one of the adenocarcinoma markers and negative calretinin staining is highly specific and sensitive for identifying adenocarcinoma in fluid cytology.