Euonymus europaeus L.(Celastraceae)(EE), known as spindle tree, is a deciduous shrub commonly found all over European continent, used in traditional medicine for the treatment of ectoparasites. The present study investigates the in vitro anticancer effects of EE hydro-alcoholic extract prepared from fresh fruits. Qualitative and quantitative analysis of the EE extract content where made by high-performance liquid chromatography coupled with mass spectrometry (HPLC-MS). Cell Proliferation Assay and Anexin V-fluorescein isothiocyanate apoptosis detection where performed on both human melanoma cell line and normal human fibroblasts, in serial doses ranging from 0.05 µg/mL up to 50 µg/mL, at 6 and 24 hours exposure. Evodiamine, a potent anticancer compound was found in significant amounts. In vitro melanoma cells were inhibited in a concentration-dependent manner (p< 0.001),(IC50= 6.76 µg/mL), and they were almost ten-fold more sensitive than fibroblasts (IC50= 53.08 µg/mL). EE had a significant and selective antitumor activity.