AMEP (for Antiangiogenic MEtargidin Peptide) is a novel anti-cancer agent exerting anti-proliferative and anti-angiogenic effects by binding to αvβ3 and α5β1 integrins. Electrotransfer designates the use of electric pulses (electroporation) to transfer plasmid DNA into tissues. This first-in-man phase I study investigated safety and tolerability of intratumoural plasmid AMEP electrotransfer into cutaneous metastatic melanoma. Secondary objectives were efficacy and pharmacokinetics. Five patients with disseminated melanoma without further treatment options were treated at two dose levels (1 and 2 mg DNA). In each patient, two cutaneous lesions were identified (one treated, one control). At day 1 and day 8, plasmid AMEP was injected intratumourally followed by electrotransfer. Patients were monitored weekly until day 29, and at day 64. Local efficacy was assessed at day 29 by direct measurement, and post-treatment biopsies for AMEP mRNA levels by RT-QPCR. Plasmid copy number in blood and urine was determined by QPCR. Minimal systemic toxicity was observed including transient fever and transitory increase in C-reactive protein. No related serious adverse events occurred. Plasmid AMEP was detected in plasma, but not urine. AMEP mRNA was found in 3 of 5 treated lesions and none of control lesions. At day 29, all 5 treated lesions were stable in diameter, whereas 4 of 5 control lesions increased over 20 %. No response occurred in distant lesions. This first-in-man study on electrotransfer of plasmid AMEP into cutaneous melanoma shows that the procedure and drug are safe, and that local transfection was obtained.