The overexpression of phosphorylated signal transducer and activator of transcription-3 (p-STAT3) and phosphorylated extracellular signal-regulated kinase (p-ERK) have recently been shown to play an important role in the pathogenesis of various human tumors. However, the role of these two major signal transduction pathways in dermatofibrosarcoma protuberans (DFSP) remains unknown. This study was designed to investigate the significance of p-STAT3 and p-ERK expression in DFSP. The expressions of p-STAT3 and p-ERK were analyzed by immunohistochemical staining in formalin-fixed, paraffin-embedded tissue sections of human DFSP and dermatofibroma. Ten cases were positive for p-STAT3 expression in 14 cases of DFSP, however, only 5 cases were positive in 20 cases of dermatofibroma. Eleven out of 14 cases of DFSP expressed p-ERK, but only four cases were positive in 20 cases of dermatofibroma. The expressions of p-STAT3 and p-ERK were significantly higher than those in dermatofibroma (both p < 0.01). This study suggests that the overexpression of p-STAT3 and p-ERK may play a pivotal role in the oncogenesis of DFSP.