Normal and reactive non-neoplastic serosal tissues and a spectrum of serosal neoplasms were studied using lightmicroscopic, ultrastructural, immunocytochemical, gel electrophoretic, and immunoblot techniques. Normal surface mesothelium expressed both low- and high-molecular- weight cytokeratins, whereas the scattered submesothelial cells were decorated only with antibodies to vimentin. Reactive non-neoplastic subserosal cells, however, coexpressed both low-molecular-weight cytokeratin and vimentin and demonstrated the ability for surface differentiation during which higher-molecular-weight cytokeratins were acquired and vimentin was lost. The authors suggest the term “multipotential subserosal cells,” recognizing the unique intermediate filament expression of reactive subserosal cells and the ability for surface differentiation. The intermediate filament expression of the sarcomatoid/desmoplastic mesotheliomas resembled the MSC, whereas epithelial mesotheliomas resembled surface mesothelium. These findings have potential usefulness for diagnostic pathology.