Activation of PPARgamma by synthetic ligands, thiazolidinediones, inhibits the proliferation of cancer cells. In this report, focusing our attention on ciglitazone, we show that ciglitazone inhibits melanoma growth by inducing apoptosis and cell-cycle arrest, whereas normal melanocytes are resistant to ciglitazone. In melanoma cells, ciglitazone-induced apoptosis is associated with caspase activations and a loss of mitochondrial membrane potential. Induction of cell-cycle arrest by ciglitazone is associated with changes in expression of key cell-cycle regulators such as p21, cyclin D1, and pRB hypophosphorylation. Cell-cycle arrest occurs at low ciglitazone concentrations and through a PPARgamma-dependent pathway, whereas the induction of apoptosis is caused by higher ciglitazone concentrations and independently of PPARgamma. These results allow an effective molecular dissociation between proapoptotic effects and growth inhibition evoked by ciglitazone in melanoma cells. Finally, we show that in vivo treatment of nude mice by ciglitazone dramatically inhibits human melanoma xenograft development. The data presented suggest that ciglitazone might be a better candidate for clinical trials in melanoma treatment than the thiazolidinediones currently used in the treatment of type 2 diabetes, such as rosiglitazone, which is devoid of a proapoptotic PPARgamma-independent function.