Melanoma cells often display constitutive expression of the major histocompatibility complex (MHC) class II molecules which is associated with a higher metastatic dissemination. The MHC class II molecules during T cell/ professional antigen-presenting cell (APC) interactions are localized, as signalling receptors, into membrane lipid rafts which are thought to be sites of signalling complex assembly. Therefore, with the aim of understanding the molecular mechanisms used by melanoma cells to frustrate an effective anti-tumour response we stimulated a MHC class II constitutive expressing melanoma cell line with a specific antibody that mimics the interaction of T-cell receptor (TCR) with class II molecules. In stimulated melanoma cells we showed through Western blotting and immunofluorescence experiments the recruitment of HLA-DR molecules in lipid raft compartments as well as the c-Jun NH2-terminal kinase activations as a consequence of the class II engagement. Furthermore, we showed that SDS-stable HLA-DR-peptide complexes are recruited in lipid rafts of stimulated melanoma cells. Therefore, in light of the results reported, our hypothesis is that the redistribution of class II molecules into lipid raft microdomains of stimulated melanoma cells as well as the associated activation of signalling pathways, could be useful for melanoma cells to frustrate an effective anti-tumour response.