Pulmonary sclerosing hemangioma (SH) is an unusual tumor of pneumocytic origin. Morphologically, SH can mimic pulmonary adenocarcinomas. Here, the authors compared genetic and epigenetic aberrations in SH with those in pulmonary adenocarcinoma. Clinicopathologic characteristics, microsatellite alterations, and CpG island methylation were analyzed in pulmonary SHs (n = 24) and adenocarcinomas (n = 34) to compare their patterns of molecular abnormalities. SHs were also analyzed immunohistochemically to characterize the expression status of proteins involved in basic biologic processes. The clinical presentation of SH cases was generally benign. Both cell types of SH stained positive for thyroid transcription factor 1 (TTF-1), epithelial membrane antigen (EMA), β-catenin, E-cadherin, and vascular endothelial growth factor (VEGF). Allelic imbalances in D3S1283, D3S1234, D3S1300, D3S1285, TP53, D17S938, and D9S179 were less frequent in SH than in adenocarcinoma; rates of allelic imbalances in D20S170 and D21S1446 were not significantly different. In SH, CpG island methylation frequencies of p16(INK4a) (0.0%) and RASSF1A (12.5%) were significantly lower than those in adenocarcinoma (29.4% and 38.2%, respectively); the frequencies of HOX D9, D11, and D13 gene methylation in SH were 37.5%, 33.3%, and 33.3%, respectively. The results show that pulmonary SH and adenocarcinoma share similar genetic and epigenetic aberrations, but also exhibit significant differences, especially in tumor suppressor genes.