Spontaneous regression of melanoma lesions is thought to be the result of an efficient immune response against melanoma cells in vivo. The outcome of immune responses is critically influenced by a complex network of interacting cytokines present in the local microenvironment. Analysis of cytokine gene transcription in melanoma lesions exhibiting or lacking a sufficient anti-tumor immune response thus may help to define cytokines or cytokine combinations critical to the development of this immune response. In the present study, we have investigated an extended panel of cytokine and cytokine receptor genes by reverse transcription-PCR and in situ hybridization in regressive and progressive primary human cutaneous melanoma samples. Whereas the presence of a lymphocyte infiltrate in tissue samples was associated with a TH1 cytokine mRNA profile (TNF-alpha, INF-gamma, IL12p35, IL12p40, IL2Rbeta, and IL2Rgamma), clinically and histologically regressive samples exhibited additionally increased transcript levels for GM-CSF, IL2, and IL15. mRNAs of TH2 cytokines IL4 and IL5 were detected only in a minor portion of progressive melanoma samples and regressive melanoma lesions. These results were further supported by comparison of progressive with regressive regions in three melanoma samples. Again, regressive regions contained higher transcript levels for GM-CSF, IL2, and IL15. In comparison to cutaneous metastatic melanoma lesions, regressive melanomas also overexpressed the same cytokine mRNA profile. These results provide evidence for an association of spontaneous regression with increased transcript levels for the cytokine combination GM-CSF, IL2, and IL15 in malignant melanoma. This cytokine combination could be relevant for experimental anti-tumor immune response studies and for immunotherapeutic and gene transfer studies in the treatment of melanoma patients.