Current treatment for advanced, metastatic melanoma is not very effective, and new modalities are needed ADI-PEG20 is a drug that specifically targets ASS-negative malignant melanomas while sparing the ASS-expressing normal cells Although laboratory research and clinical trials showed promising results, there are some ASS-negative cell lines and patients that can develop resistance to this drug In this report, we combined ADI-PEG20 with another antitumor drug TRAIL to Increase the killing of malignant melanoma cells This combination can greatly inhibit cell growth (to over 80%) and also enhanced cell death (to over 60%) in four melanoma cell lines tested compared with control We found that ADI-PEG20 could increase the cell surface receptors DR4/5 for TRAIL and that caspase activity correlated with the increased cell death These two drugs could also increase the level of Noxa while decrease that of survivin We propose that these two drugs can complement each other by activating the intrinsic and extrinsic apoptosis pathways, thus enhance the killing of melanoma cells Published by Elsevier Inc