Hypoxic pelvic and limb perfusion by means of a balloon occlusion technique was evaluated in patients with recurrent melanoma of the lower limbs who were non-responders to isolated hyperthermic limb perfusion or who were not eligible for this procedure. A pilot study was performed in 17 patients, who underwent hypoxic pelvic and limb perfusion with 50 mg/m2of melphalan or 50 mg/m2of melphalan and 25 mg/m2of mitomycin C. Each procedure was followed by haemofiltration. A leakage monitoring study was performed in five of the 17 patients. The response rate and time to disease progression were the primary endpoints, with overall survival as the secondary endpoint. During the procedures there were no technical, haemodynamic or vascular complications, and no deaths occurred during surgery or in the postoperative period. Significant leakage (median 40%) was measured in the five patients studied. No severe systemic or regional toxicity was observed. After one course of treatment, the objective response rate was 47% (95% confidence interval 22.5–71.5%), the median time to disease progression was 10 months (range 2–40 months), and the 3 year overall survival was 20%. Hypoxic pelvic and limb perfusion seems to be a safe and effective treatment for patients with unresectable recurrent limb melanoma who are not eligible for isolated hyperthermic limb perfusion. Due to the non-homogeneity of the study, with some patients receiving a combination of melphalan and mitomycin C and others receiving only melphalan, it is not possible to make definite conclusions with regard to efficacy. Further studies are necessary to establish whether the response rates can be improved by using different drug regimens.