The use of monoclonal antibody 44-3A6 in cell blocks in the diagnosis of lung carcinoma, carcinomas metastatic to lung and pleura, and pleural malignant mesothelioma. Monoclonal antibody (MoAb) 44-3A6 recognizes a glandular differentiation-associated antigen and has been used to identify exocrine differentiation in pulmonary carcinomas. The authors assessed its value in the diagnosis of lung carcinomas metastatic to lung/pleura and pleural malignant mesothelioma (MM), using cell blocks derived from cytologic specimens. Sixty-three primary lung carcinomas, 31 metastatic adenocarcinomas (ACs) (from breast, gastrointestinal tract, or genitourinary tract), and 36 MMs were immunostained with 44-3A6, Leu-M1, and anti-carcinoembryonic antigen (CEA). The results confirm the value of 44-3A6 in identifying ACs but do not allow distinction between those of pulmonary, breast, GIT, or ovarian mucinous derivation. Endometrial, ovarian serous, and renal ACs are essentially nonreactive, as are almost all MMs. The occurrence of one positive MM predicates caution in interpreting 44-3A6 positivity in isolation, but, judiciously used with other discriminating antibodies such as Leu-M1 and anti-CEA, 44-3A6 is of value in the differential diagnosis of ACs and MMs. Further, its applicability to cytologic specimens may obviate the need for more invasive diagnostic procedures and lead to rapid, accurate diagnosis. 