To assess the clinicopathologic features, differential diagnosis, and pathogenesis of sclerosing angiomatoid nodular transformation (SANT) of the spleen.The clinical characteristics of 7 cases with SANT were retrospectively analyzed. Histochemical and immunohistochemical (EnVision method) examinations were performed. Moreover, quantitative assessment of IgG4 and IgG-positive cells was performed.The 7 SANT patients included 1 female and 6 males, with ages ranging from 7 to 60 years (mean 33.4 years). They showed no specific clinical manifestations. Macroscopically, the surface of the excised masses was gray-white, and vague nodularity was observed. Mass sizes ranged from 3.0 to 7.0 cm (mean 5.5 cm). Microscopically, all cases were characterized based on multiple angiomatoid nodules of various sizes embedded in a fibrosclerotic stroma. The nodules were round and sometimes convoluted. Moreover, the nodules were composed of slit-like, irregularly-shaped, or slightly dilated vascular spaces lined by plump endothelial cells, and interspersed with a population of spindly or ovoid cells. Immunohistochemical examination showed a heterogeneous staining pattern, with the lining cells of small capillaries expressing CD34 and those of sinusoid-like structures expressing CD8. CD31 was stained in the lining and interspersed cells, thus resulting in a complex meshwork. Additionally, the lining cells were focally positive for CD68. Vimentin and smooth muscle antibody were expressed in all 7 cases, whereas no desmin or CD21 was detected. IgG4-positive cells accounted for 2 to 5 per high-power field (mean 3.7). Furthermore, the IgG-positive cells accounted for 2 to 8 per high-power field (mean 4.2).SANT is a rare primary benign tumor-like lesion of the spleen, and has characteristic histopathological features and immunohistochemical profiles. SANT should be distinguished from other angiomatoid tumors and tumor-like lesions. Moreover, SANT could be treated by splenectomy, with favorable prognosis. The relationship between SANT and IgG4-related sclerosing lesions remains to be clarified.