In this study we used TEPITOPE, a new epitope prediction software, to identify sequence segments on the MAGE-3 protein with promiscuous binding to histocompatibility leukocyte antigen (HLA)-DR molecules. Synthetic peptides corresponding to the identified sequences were synthesized and used to propagate CD4⁺ T cells from the blood of a healthy donor. CD4⁺ T cells strongly recognized MAGE-3_281–295 and, to a lesser extent, MAGE-3_141–155 and MAGE-3_146–160. Moreover, CD4⁺ T cells proliferated in the presence of recombinant MAGE-3 after processing and presentation by autologous antigen presenting cells, demonstrating that the MAGE-3 epitopes recognized are naturally processed. CD4⁺ T cells, mostly of the T helper 1 type, showed specific lytic activity against HLA-DR11/MAGE-3–positive melanoma cells. Cold target inhibition experiments demonstrated indeed that the CD4⁺ T cells recognized MAGE-3_281–295 in association with HLA-DR11 on melanoma cells. This is the first evidence that a tumor-specific shared antigen forms CD4⁺ T cell epitopes. Furthermore, we validated the use of algorithms for the prediction of promiscuous CD4⁺ T cell epitopes, thus opening the possibility of wide application to other tumor-associated antigens. These results have direct implications for cancer immunotherapy in the design of peptide-based vaccines with tumor-specific CD4⁺ T cell epitopes.