Metastatic melanoma confined to a limb can be treated effectively by isolated limb infusion (ILI) with cytotoxic drugs. The present study was undertaken to determine whether electively performing a second ILI procedure after 4 weeks increases the frequency and/or duration of response, and also to assess the value of a second ILI when disease recurrence or progression in a limb occurs after a first ILI. In 47 patients, a planned double ILI protocol achieved an overall response (OR) rate of 88% (complete response (CR) 41%, partial response (PR) 47%, median duration of response 18 months). Response rates after double ILI were similar to those in 81 patients treated with a single ILI over the same time period (CR 41%, PR 41%), without significant differences in response duration. After double ILI more patients experienced Wieberdink Grade III or IV limb toxicity. Following a second ILI for progression after an initial ILI (n=14), the OR rate was 71%, with a 5 month median duration of response. Since elective double ILI increases toxicity without increasing efficacy, performance of a single ILI is the preferred treatment option for melanoma confined to a limb. However, a second ILI can be of value if limb disease recurs or progresses following a previous ILI.