It is generally considered that MHC class I-restricted antigens are recognized by CD8⁺ T cells, whereas MHC class II-restricted antigens are recognized by CD4⁺ T cells. In the present study, we report an MHC class I-restricted CD4⁺ T cell isolated from the tumor infiltrating lymphocytes (TILs) of a patient with metastatic melanoma. TIL 1383 I recognized HLA-A2⁺ melanoma cell lines but not autologous transformed B cells or fibroblasts. The antigen recognized by TIL 1383 I was tyrosinase, and the epitope was the 368–376 peptide. Antibody blocking assays confirmed that TIL 1383 I was MHC class I restricted, and the CD4 and CD8 coreceptors did not contribute significantly to antigen recognition. TIL 1383 I was weakly cytolytic and secreted cytokines in a pattern consistent with it being a T_h1 cell. The avidity of TIL 1383 I for peptide pulsed targets is 10–100-fold lower than most melanoma-reactive CD8⁺ T cell clones. These CD4⁺ T cells may represent a relatively rare population of T cells that express a T-cell receptor capable of cross-reacting with an MHC class I/peptide complex with sufficient affinity to allow triggering in the absence of the CD4 coreceptor.