AIM: Electrochemotherapy (ECT) combines chemotherapy with an electric pulse to directly target tumor cells by increasing cell membrane permeability, facilitating the efficient uptake of chemotherapeutic agents by tumor cells and improving their therapeutic efficacy. It is widely used for treating skin metastatic nodules or metastases of subcutaneous tissue. Therefore, the aim of this study is to report the experience regarding the use of ECT in a tertiary referral hospital and explore its safety and efficacy in treating skin cancer. METHODS: This study included 97 skin cancer patients treated with ECT at the Surgical Oncological Unit of the University of Perugia, Italy, between 2013 and 2024. ECT was performed using the Cliniporator® device (model EP02, IGEA, Carpi, Italy). The individuals with life expectancy greater than three months and American Society of Anesthesiologists physical status classification of I–III were included in this study, while those with arrhythmia and allergies to bleomycin were excluded. RESULTS: In this study, melanoma was the most frequently observed malignancy, accounting for 47.4% of all cases. A total of 46 melanoma patients aged between 42 and 93 years underwent ECT treatment. Most of these patients presented with in-transit metastases (67.4%) and often had multiple lesions (71.74%). Furthermore, 21 patients received only one session, while 25 underwent multiple sessions. Almost all procedures were performed with intravenous administration of bleomycin. However, in two cases, intralesional cisplatin was used for a recurrence of melanoma localized in the scalp. Notably, no adverse events were observed during ECT procedure. Moreover, most of the patients (70.45%) were alive one year after the first ECT session. The 5-year probability of survival was 24% after the first ECT session. CONCLUSIONS: Electrochemotherapy represents a safe and effective therapeutic strategy for various malignancies, with significant potential for future clinical applications.