In cancer, spontaneous apoptosis of circulating peripheral blood lymphocytes (PBLs) is a general phenomenon. In this study we aimed to determine whether spontaneous apoptosis of circulating PBLs of patients with malignant melanoma occurs. Pathologically proven 45 patients with malignant melanoma and 19 healthy controls were included in this study. Samples were obtained both on first admission before treatment, either adjuvant or metastatic, and follow-up period of patients. Human active caspase-3 immunoassay (R&D Systems, Inc. MN, USA) employs the quantitative sandwich enzyme immunoassay technique. A monoclonal specific for caspase-3 has been used. The spontaneously apoptotic PBLs in melanoma patients were not significantly different from those obtained for normal controls (p = 0.25). None of the clinical characteristics were significantly correlated with spontaneous apoptosis (p > 0.05). Likewise, we found that apoptosis in PBLs was not a prognostic factor in melanoma patients (p = 0.79). In conclusion, we did not observe accelerated apoptosis of PBLs in patients with melanoma. Further studies are necessary to determine the potential prognostic importance of this observation.