Natural killer receptors are expressed both on natural killer populations and subpopulations of T cells, mainly α/β TCR⁺CD8⁺ T cells. We have characterized the expression of the C-type lectin natural killer receptor CD94/NKG2 on tumor-infiltrating lymphocytes in primary and metastatic melanoma lesions. By immunohistochemistry, 5–10% of the tumor-infiltrating lymphocytes, both in primary and metastatic lesions, expressed CD94. More than 95% of these CD94⁺ cells coexpressed CD8 and the percentage of CD94 expression within the CD8⁺ cell population ranged from 5 to 20% with a higher expression in metastatic lesions. CD94/NKG2 exists both in an inhibitory and an activating form; thus, it was necessary to determine whether the inhibitory CD94/NKG2-A/B, the activating CD94/NKG2-C/E, or both were expressed on tumor-infiltrating lymphocytes. Reverse transcription–polymerase chain reaction using specific primers for NKG2-A/B and C/E mRNA revealed the presence of NKG2-C/E in all primary and metastatic lesions. In contrast, the inhibitory NKG2-A/B was only present in 50% of primary tumors whereas 80% of tumor-infiltrating lymphocytes in metastatic lesions expressed these transcripts. In healthy humans, the mean number of inhibitory natural killer receptors is higher than that of activating receptors, but the opposite was true for tumor-infiltrating lymphocytes in melanoma. The reversal of the ratio of inhibitory to activating natural killer receptors among tumor-infiltrating lymphocytes suggests a regulated event due to either specific factors within the tumor microenvironment, preferential homing of T cell subsets, or certain stages of T cell activation.