We studied the peripheral representation, in vitro expansion, cytokine production, and cytotoxicity of gamma delta T lymphocytes from 23 patients with cutaneous primary melanoma and 28 healthy subjects. We demonstrated that the absolute number and the percentage of circulating gamma delta + T cells were significantly reduced in melanoma patients in comparison with healthy subjects. The decrease was due to a reduction of V delta 2 T cells, whereas the number of V delta 1 T cells was not affected. As a consequence, the V delta 2/V delta 1 ratio was inverted in melanoma patients. A lower percentage of gamma delta + T cells producing tumor necrosis factor-alpha or interferon-gamma was found in melanoma patients. After a 10 d in vitro culture, both the percentage and the expansion index of gamma delta T cells, and in particular of V delta 2 subset, were significantly reduced in melanoma patients in comparison with healthy subjects. The cytotoxicity of sorted gamma delta T cells against tumor cell lines and the percentage of gamma delta T cells producing perforins were preserved in melanoma patients. The numerical and functional impairment of gamma delta T cells could contribute to the inadequate immune response found in melanoma patients and offers the potentiality for the planning of new approaches of immune therapy of malignant melanoma.