Calretinin is an intracellular calcium-binding EF-hand protein of the calmodulin superfamily. It plays a role in diverse cellular functions, including message targeting and intracellular calcium signaling. It is expressed in the mesothelium, mast cells, some neural cells, and fat cells, among others. Because of its relative specificity for mesothelial neoplasms, calretinin is widely used as one of the primary immunohistochemical markers for malignant mesothelioma and in differentiating it from adenocarcinoma. On the basis of our sporadic observation on calretinin immunoreactivity in desmoid fibromatosis, we systematically evaluated calretinin, keratin cocktail (AE1/AE3), and WT1 immunoreactivity in 268 fibroblastic/myofibroblastic neoplasms. Calretinin was observed in 75% (44/58) of desmoid fibromatosis, 50% (21/42) of proliferative fasciitis, 23% (8/35) of nodular fasciitis, 33% (13/40) of benign fibrous histiocytoma, 35% (22/62) of malignant fibrous histiocytoma, and 13% (4/31) of solitary fibrous tumors but not in normal connective tissue fibroblasts at various sites. Keratin AE1/AE3 immunoreactivity was also commonly (6/13) present in the large ganglion-like cells of proliferative fasciitis and sometimes in nodular fasciitis (3/35), solitary fibrous tumor (3/27), and malignant fibrous histiocytoma (9/62). Nuclear immunoreactivity for WT1 or keratin 5 positivity was not detected in myofibroblastic tumors. On the basis of these observations, it can be concluded that calretinin and focal keratin immunoreactivity is fairly common in benign and malignant fibroblastic and myofibroblastic lesions. Calretinin-positive and keratin-positive spindle cells in desmoid and nodular fasciitis or calretinin-positive ganglion-like cells in proliferative fasciitis should not be confused with elements of epithelioid or sarcomatoid mesothelioma. These diagnostic pitfalls can be avoided with careful observation of morphology, quantitative differences in keratin expression, and use of additional immunohistochemical markers such keratin 5 and WT1 to verify true epithelial and mesothelial differentiation typical of mesothelioma.