Dermatofibrosarcoma protuberans (DFSP) is an intermediate malignancy of the skin. Although COL1A1/PDGFB fusion gene was identified in the tumor cells recently, not all of the cases were positive for the fusion gene, and further researches are still needed to clarify the pathogenesis of DFSP. In this study, we investigated the role of microRNAs in the tumor. microRNA PCR array showed several microRNAs increased or decreased in DFSP in vivo compared with dermatofibroma (DF) and normal skin. Among them, the expression of miR-205 was down-regulated in DFSP compared with DF and normal skin. In situ hybridization showed that miR-205 expression was evident in dermal fibroblasts of normal skin although hardly detected in tumor cells of DF or DFSP. miR-205 inhibitor increased cell proliferation and the luciferase activity of 3'UTR of low-density lipoprotein receptor-related protein-1 (LRP-1) in cultured normal dermal fibroblasts. Immunohistochemistry showed the expression of LRP-1 was increased in DFSP tissue. Knockdown of LRP-1 suppressed cell growth and down-regulated extracellular signal-regulated kinase (ERK) phosphorylation without affecting MEK phosphorylation in cultured DFSP cells. Taken together, LRP-1 overexpression caused by the miR-205 down-regulation may play a role in the abnormal proliferation of DFSP cells via directly regulating ERK phosphorylation.