In-transit metastases of melanoma occur in 5-8% of all melanoma patients. In case of extensive locoregional disease, Tumor necrosis factor- and melphalan-based isolated limb perfusion (TM-ILP) had proven to yield excellent local control. Here, we report on repeat TM-ILP for locoregional recurrence after isolated limb perfusion. Between 1991 and 2013, 37 consecutive repeat TM-ILPs were analyzed in 32 different patients. Three patients underwent a third TM-ILP. During a median follow-up of 20 months after repeat TM-ILP, the overall response rate was 86%. Complete response (CR) was recorded after 24 TM-ILPs (65%). CR after first TM-ILP was a strong predictor for successful repeat TM-ILP in terms of clinical response and local recurrence. Local toxicity was mild (70% Wieberdink I-II). The local recurrence rate was 59%. Five-year overall survival was 35%. Repeat TM-ILP is a safe treatment modality in melanoma patients with recurrent in-transit metastases of melanoma. Those with a CR after first TM-ILP benefit the most from repeat TM-ILP.