Lymphocytes infiltrating solid tumors can be propagated in vitro with interleukin 2 and are then capable, as CD8+ cytotoxic T-cells, of specific lysis of autologous tumor targets in a class I-restricted manner. Since the specificity of these cells is determined by their T-cell receptor (TCR) configuration, the aim of this study was to delineate the TCR V alpha repertoire of tumor-infiltrating lymphocytes within 24 melanoma specimens and to compare these data with the TCR expression pattern of unaffected peritumoral and normal human skin. While lymphocytes within all skin specimens tested expressed a substantial, albeit limited, heterogeneity of V alpha specificities with an average number of 9.0 different V alpha gene segments, the V alpha repertoire within cutaneous melanoma lesions was significantly more restricted (mean of V alpha expression, 3.86; P < 0.001) with a predominance of only 3 V alpha families (V alpha 13, V alpha 15, and V alpha 16), all of which were also found to be expressed within normal skin. Collectively, the fact that the TCR V alpha repertoire in melanoma is skewed toward the predominance of only a few V alpha regions may be indicative of a limited number of melanoma-associated antigenic determinants being involved in the anti-tumor immune response.