Objective: To investigate the histogenesis and differential diagnosis of pulmonary sclerosing hemangioma (PSH).Methods: Thyroid transcription factor-1 (TTF-1), surfactant proteins A, B (SP-A, SP-B), epithelial membrane antigen (EMA),vimentin, pancytokeratin, cytokeratin7 (CK7), CK5/6, calretinin, S-100, neurospecific enolase (NSE), synaptophysin (Syn),chromogranin A (CgA), CD34, factor-Ⅷ-related antigen (F-Ⅷ) and smooth muscle actin (SMA) in 55 patients with PSH were examined with immunohistochemistry, while samples from 19 patients were also observed by electron microscope. Followup information were reviewed. Results: Pathologically, PSH mainly consisted of both surface lining cuboidal cells and pale polygonal cells. Immunohistochemitry revealed that coexpression of TTF-1, EMA and vimentin in both cuboidal and polygonal cells was 94.5 % (52/55), 90.5% (50/55) and 58.2% (32/55), respectively. In cuboidal cells, the expression of SP-A and SP-B was 92.7% (51/55) and 81.8 % (45/55), respectively. Whereas pancytokeratin and CK7 immunostained the cuboidal cells in all cases. The polygonal cells were difussed immunostained with Syn in 13 PSHs (24%) and NSE in 8 PSHs (15%), while immunoreactions with S-100 and CgA were separated detected in 7 PSHs (13%). There was no significant difference of TTF-1and EMA expression between these two cells (X2 value was 1.371 and 3.352, respectively. P ＞ 0.05). in contrast, there was a significant difference of vimentin between them (X2 value was 17.720, P ＜ 0.001 ). Electron microcopy observation showed that ultrastructure may not differ from each other sometime. The follow-up was obtained for 49 cases ranged from 3 months to 14years. 48 of them had no recurrence or metastasis except one case had recurrence. Conclusion: PSH may origin from the primitive respiratory epithelial. Polygonal and cuboidal cells are all parenchymal neoplasm cells. The concomitant examination of TTF-1, SPA, SP-B, EMA, vimentin and pancytokeratin may favor the diagnosis and differential diagnosis of PSH.