Various clinical and experimental observations point to the existence of an immunological host defense in cutaneous malignant melanoma. To identify the major effector mechanisms mediating the specific anti-tumor immune response, we examined 23 benign and neoplastic melanocytic lesions (3 nevi, 14 primary melanomas, and 3 cutaneous and 3 systemic metastases) by quantitative immunohistology, and correlated these results with the histopathological and clinical subtypes of malignant melanoma. Our analyses indicate that CD3+ T-cell receptor alpha/beta-expressing lymphocytes are the prevailing leukocyte subset in primary as well as secondary malignant melanoma. We further observed that in early lesions (< 0.75 mm) of superficial spreading melanoma the vast majority of tumor-infiltrating lymphocytes (TIL) belong to the CD4+ subset and frequently express CD45RA antigens. In more advanced tumors, the contribution of CD8+ TIL gradually increases, indicating that the quality of the anti-tumor immune response changes during the course of the disease. Finally, we found that a varying percentage of cutaneous TIL express the cutaneous leukocyte antigen which is defined by the monoclonal antibody HECA 452 and preferentially expressed by skin-seeking memory T cells. In contrast, extracutaneous melanoma metastases (liver, brain, ovary) were completely devoid of HECA 452-reactive lymphocytes. These findings suggest that lymphocytes infiltrating cutaneous melanomas belong to a memory/effector T-cell subset functionally associated with the skin.