The resistance of melanoma to current treatment modalities represents a major obstacle for durable therapeutic response, and thus the elucidation of mechanisms of resistance is urgently needed. The crucial functions of activating transcription factor-2 (ATF2) in the development and therapeutic resistance of melanoma have been previously reported, although the precise underlying mechanisms remain unclear. Here, we report a protein kinase C-varepsilon (PKCvarepsilon)- and ATF2-mediated mechanism that facilitates resistance by transcriptionally repressing the expression of interferon-beta1 (IFNbeta1) and downstream type-I IFN signaling that is otherwise induced upon exposure to chemotherapy. Treatment of early-stage melanomas expressing low levels of PKCvarepsilon with chemotherapies relieves ATF2-mediated transcriptional repression of IFNbeta1, resulting in impaired S-phase progression, a senescence-like phenotype and increased cell death. This response is lost in late-stage metastatic melanomas expressing high levels of PKCvarepsilon. Notably, nuclear ATF2 and low expression of IFNbeta1 in melanoma tumor samples correlates with poor patient responsiveness to biochemotherapy or neoadjuvant IFN-alpha2a. Conversely, cytosolic ATF2 and induction of IFNbeta1 coincides with therapeutic responsiveness. Collectively, we identify an IFNbeta1-dependent, cell-autonomous mechanism that contributes to the therapeutic resistance of melanoma via the PKCvarepsilon-ATF2 regulatory axis.Oncogene advance online publication, 2 March 2015; doi:10.1038/onc.2015.22.