Recent investigations indicate that malignant melanoma cells can produce distinct cytokines. While differences in the production of single cytokines have been observed among different melanoma cell lines, the extent of variability in the production of single and multiple cytokines between individual melanoma cell lines has not been as thoroughly investigated. A heterogeneity in melanoma cell cytokine production could have important implications for the biology of this aggressive neoplasm since certain cytokines may act as autocrine growth factors or be potent modulators of host immune response to the developing tumor. The purpose of this study is to assess the cytokine production profile of two widely available human melanoma cell lines, A375 and G361. The A375 cell line constitutively expressed the mRNA for IL-1 alpha, IL-1 beta and PDGF-A, with increased expression of these cytokines after induction with PMA. GM-CSF mRNA was expressed by the A375 melanoma line only after induction with PMA. No IL-6 mRNA was detected in the A375 melanoma cell line. The cell culture supernatants from the A375 cells likewise contained a parallel increase in IL-1 activity as determined in the D10 bioassay and secreted GM-CSF and PDGF-AA as measured by ELISA. In contrast, the G361 cell line did not express IL-1, GM-CSF or PDGF-A mRNA (constitutively or after PMA induction) but expressed only IL-6 mRNA and secreted IL-6 activity after PMA induction. These results demonstrate a significant heterogeneity in the production of IL-1 alpha, IL-1 beta, IL-6, GM-CSF, and PDGF in two distinct melanoma cell lines. This study demonstrates that individual melanoma cell lines express and secrete multiple cytokines both constitutively and after stimulation with PMA. The immunodulating and mitogenic properties of these melanoma-derived cytokines may have implications in determining the biologic behavior of different malignant melanomas.