The natural ligands of the nuclear receptors vitamin D receptor (VDR) and retinoic acid receptor (RAR), i.e., 1alpha,25-dihydroxyvitamin D3 (VD) and all-trans retinoic acid, have important effects on the proliferation, differentiation and apoptosis of a variety of malignant cells, including melanoma. The therapeutic potential of the 2 nuclear hormones can be enhanced by the use of synthetic analogues. In this study, the 2 human melanoma cell lines WM1341 and MeWo were compared for the combined effect of VD and synthetic retinoids. Both cell lines expressed reasonable amounts of VDR, RARgamma and retinoid X receptor alpha and differed only in the relative expression of RARalpha and beta. From 9 functional variants of retinoids, only the RARgamma-selective retinoid CD437 showed, in both cell lines, a significant anti-proliferative effect. In MeWo cells, but not in WM1341 cells, VD induced growth arrest but showed no synergistic interaction with the effects of CD437. In contrast, VD induced apoptosis in WM1341, but not in MeWo, cells. CD437 was a strong inducer of apoptosis in both melanoma cell lines. Parallel treatment with CD437 and VD resulted in synergistic enhancement of apoptosis in WM1341 cells, whereas a clear decrease in induction of apoptosis in MeWo cells occurred. Our results indicate that a combined treatment of melanoma with VD and selected retinoids is promising but should be adapted to individual types of tumor.