The histogenesis of pulmonary sclerosing hemangioma has remained controversial despite extensive studies by many investigators. The availability of an antibody to thyroid transcription factor-1 (TTF-1), which is expressed in type II pneumocytes and Clara cells, has prompted us to readdress this issue. Sixteen cases were immunostained with a panel of antibodies including TTF-1. The patients were predominantly women with an age range of 30 to 73 years (mean, 52 yrs). All tumors were solitary. The single male patient showed regional lymph node metastases, an unusual occurrence reported only once in the literature. All cases exhibited the classic histologic features, with variegated patterns. TTF-1 expression was observed in both the surface lining cells and the pale polygonal cells. The surface lining cells were epithelial membrane antigen (EMA)+ cytokeratin+ surfactant apoprotein A+, whereas the polygonal cells were EMA+ cytokeratin- surfactant apoprotein A-. The neuroendocrine markers synaptophysin and chromogranin were both negative. The metastatic deposits in the lymph nodes comprised only polygonal cells and exhibited an EMA+ cytokeratin- surfactant apoprotein A- TTF- 1+ immunophenotype. These results suggest that pulmonary sclerosing hemangioma is an epithelial neoplasm derived from primitive respiratory epithelium or incompletely differentiated type II pneumocyte or Clara cell.