Malignant melanoma is a very metastatic and therapy resistant disease, with few therapeutic options in advanced stages. An abnormal apoptosis pathway is considered to contribute substantially to the resistance observed in melanoma patients. In this study, “close-to-patient” melanoma cell models: adherent monolayers in serum-containing media and non-adherent spheroids in stem cell media (which supposedly selects for stem-like melanoma initiating cells), were compared with respect to: the expression of anti-apoptotic molecules from the Inhibitors of Apoptosis Proteins (IAP) family; and sensitivity to the treatment with Tumor Necrosis Factor (TNF) - Related Apoptosis Inducing Ligand (TRAIL), acting through death receptor 4 and 5 (DR4 and DR5), alone or in combination with siRNA-mediated down-regulation of IAPs. Spheroids demonstrated a higher expression of IAPs (in 8 from 15 studied cases), where the IAP livin was up-regulated the most. Also a tendency for up-regulation of DR5 was shown, and the spheroid cells were more sensitive to the DR5-mediated treatment than the monolayer cells, indicating that this strategy might affect tumor initiating cells present in melanoma spheres. The treatment via DR4 had only a negligible effect. Although down-regulation of XIAP showed a small additive effect, the contribution of the XIAP or survivin knock-down to the reduced cell viability or spheroid forming capacity, was very low.