Electrochemotherapy consists of chemotherapy followed by local application of electric pulses to the tumor to increase drug delivery into the cells. The aim of this Phase II clinical study was to evaluate the antitumor effectiveness of electrochemotherapy using intratumoral cisplatin administration on cutaneous tumor nodules in malignant melanoma patients. In 10 patients, 133 tumor nodules of different sizes were treated: (a) 82 tumor nodules were treated with electrochemotherapy; (b) 27 tumor nodules were treated with cisplatin; (c) 2 tumor nodules were treated with electric pulses; and (d) 22 tumor nodules were untreated. Four weeks after therapy, 78% objective responses were obtained in the electrochemotherapy group, and 38% objective responses were obtained in the cisplatin group. Exposure of tumor nodules to electric pulses without cisplatin treatment had no effect on tumor growth. Electrochemotherapy was well tolerated by all patients, and a good cosmetic effect was obtained, with only minimal scarring and a slight depigmentation of the skin. At 124 weeks of follow-up, a 77% control rate of the tumor nodules treated by electrochemotherapy was observed, compared to 19% for those that were treated with cisplatin only (P < 0.0001). Our results clearly demonstrate that electrochemotherapy with cisplatin is a highly effective approach for treatment of cutaneous malignant melanoma nodules. The advantages of this therapy include its simplicity, the short duration of treatment sessions, low cisplatin doses, and insignificant side effects, as well as the fact that it can be done on an outpatient basis.