Melanin has emerged as an attractive target for radioimmunotherapy of melanoma, and a radiolabeled monoclonal antibody (mAb) 6D2 to melanin developed at AECC is currently in clinical evaluation. This report described two approaches to improve the targeting of radiation to tumors using melanin-binding mAbs: (a) the potency of two mAbs to melanin was compared and, (b) the impact of the administration of a chemotherapeutic agent followed by RIT was assessed in human metastatic melanoma-bearing nude mice. The study determined that the therapeutic efficacy of (188)Re-labeled 6D2 and 11B11 was comparable. Administration of DTIC followed by RIT was more effective than either modality alone. These results suggested that combining chemotherapy and immuno-radiotherapy may be an effective clinical strategy presumably due to drug-induced cell death resulting in the release of melanin and increased homing of the anti-melanin-radionuclide.