Advanced malignant melanoma is an aggressive malignancy with poor prognosis. Current therapeutic strategies have a modest success rate. The most promising treatment consists of a combination of chemotherapy with interferon‐α, but complete response rates remain less than 15%. Interferon‐α is also effective in adjuvant therapy for non‐advanced melanoma treated surgically. The molecular mechanisms leading to loss of growth restraints and gain of growth‐promoting functions during carcinogenesis of malignant melanoma are not understood in detail. Here, we studied 9 human melanoma cell lines with regard to growth inhibition by interferon‐α and defects in intracellular signal transduction through the Jak‐STAT pathway. In 3 cell lines, we found a complete loss of growth restraint by interferon‐α. In all of them, different components of the Jak‐STAT pathway were defective. Since signal transduction through the Jak‐STAT pathway is necessary for antiviral and antiproliferative effects of interferons, we conclude that defects in this pathway may be one of the mechanisms that lead to cancer progression through loss of growth‐restraining functions. Moreover, our results indicate that a subgroup of melanomas could be completely resistant to interferon‐α and should therefore not be treated with this cytokine. Int. J. Cancer 85:720–725, 2000. © 2000 Wiley‐Liss, Inc.