Targeting molecules involved in tumor invasion may be useful in future strategies for melanoma treatment aiming to reduce the progression of the disease and prevention of metastatic spread. During melanoma progression to metastatic disease, a significant overexpression of melanoma cell adhesion molecule CD146 occurs. It has been correlated with tumor progression and metastatic potential. Various approaches for targeting CD146 in melanoma cells have been exploited and CD146 has been shown to be a promising target for antitumor therapy. In our study, a new approach of gene electrotransfer (GET) of small interfering RNA (siRNA) against CD146 was evaluated in human malignant melanoma cells. We demonstrated for the first time that downregulation of CD146 mRNA after GET is more significant than after lipid-mediated transfer. Furthermore, reduced cell migration and invasion of melanoma cells was observed after GET of therapeutic siRNAs. GET of therapeutic siRNAs also reduced cell survival, but had no effect on cell proliferation. These findings suggest that targeting CD146 expression by GET of siRNAs against CD146 is effective for reducing the metastatic potential of melanoma cells in vitro. CD146 is therefore a potential target for the development of adjuvant therapies for metastatic melanoma.