CD4⁺ T cells can recognize “self” tumor antigens, but the impact of tumor cell expression of self-antigens on CD4⁺ T-cell function in humans is unknown. Here, we identify a new epitope (ISPNSVFSQWRVVCDSLEDYD) derived from tyrosinase-related protein-1 (TRP-1) using a predictive algorithm and mice transgenic for a chimeric HLA-DRB1*0401 molecule. We then compared the functions of TRP-1-epitope-specific, CD4⁺ T-cell responses in normal healthy individuals to those found in patients with metastatic malignant melanoma. Surprisingly, we found that tumor-bearing patients had significantly higher levels of TRP-1-specific, CD4⁺ T-cell function than healthy volunteers as measured ex vivo. Thus, the net effect of “self” antigen expression by tumor cells was the enhancement of tumor antigen-specific CD4⁺ T-cell function, rather than immunosuppression. These findings indicate that antigens expressed by malignant melanoma cells can partially activate CD4⁺ T lymphocytes.