The authors report two extremely unusual cases in which metastatic cancer was mimicked by mesothelial cell inclusions in mediastinal lymph nodes. The cells appeared only in the nodal sinuses and occurred predominantly as single individual cells and small clusters. The nuclei were bland, the N/C ratio was low, and the cell borders were well defined. So-called mesothelial windows were noted when cells formed groups; mitoses were not observed. Immunohistochemical analysis demonstrated the inclusions to be positive for cytokeratin (both AE1/3 and CAM5.2) but negative for epithelial membrane antigen, Leu-M1, and carcinoembryonic antigen. Nearly all cells were negative for B72.3; rare cells in one case contained unusual minute granular dot-like positivity in the region of the Golgi for this marker. The pattern of cytokeratin immunoreactivity was consistent with a mesothelial cell: namely, stronger immunoreactivity in a perinuclear location with some fading at the cell periphery. Ultrastructural analysis of both cases documented long microvilli processes consistent with a mesothelial origin. An extensive clinical workup in each case has failed to identify a primary carcinoma. It is interesting that both patients had a pleuritis with pleural effusion and both had mediastinal widening. In the first case, the exact cause of the benign pleural process was unknown but thought to be infectious. The second patient had follicular lymphoma in the same lymph node together with pleural involvement clinically and evidence of congestive heart failure. The patients are alive three years and ten months from diagnosis, respectively. Recognition of this new and previously unrecognized entity is important to prevent a diagnosis of carcinoma in such rare instances.