Advanced steps of tumor progression are generally characterized by an increased growth fraction within the neoplastic cell population. The presence of a relevant growth fraction is also related to widely accepted prognostic parameters in some human malignancies. Our aims were to evaluate the presence of a growth fraction with Ki67 monoclonal antibody (MoAb), and to correlate it with tumor progression and HLA-DR antigen expression in 88 melanocytic lesions. The lesions were 19 acquired melanocytic nevi, 58 primary melanomas [divided into 26 superficial spreading melanomas (SSM), 24 superficial spreading melanomas with nodular areas (SS + NM), and five nodular melanomas (NM)], and 11 metastases from malignant melanomas. Ki67 MoAb stained 16%, 19%, 71%, 100%, and 82% of nevi, SSM, SS + NM, NM, and metastases, respectively. Among primary melanomas, Ki67 MoAb stained 12%, 28%, 50%, and 70% of tumors less than 0.75, 0.75-1.49, 1.5-2.9, and greater than or equal to 3 mm thick, respectively. A concordant reactivity pattern for Ki67 and HLA-DR antigens was found in 72% of lesions (p less than 0.0001). We have shown that a representative growth fraction (ie, Ki67 reactivity) is present in melanocytic lesions only in advanced steps of tumor progression and correlates with HLA-DR antigen expression. Despite the different biologic values of Ki67 and HLA-DR antigens, we suggest the joint evaluation of both antigens as a useful marker of aggressive behavior in melanoma.