Monoclonal antibodies (MoAbs) against six well-defined progression-associated melanoma antigens (PAMAs) and a MoAb against the nuclear proliferation-associated antigen Ki67 were used for an immunoperoxidase study on 44 biopsies from 36 congenital melanocytic nevi (CMN). Twenty-nine common acquired nevi and 16 metastasizing primary melanomas were studied as controls. Two CMN of the series were giant CMN (greater than 20 cm), one of which later progressed to metastasizing melanoma. Of the remaining 34 CMN, four were histologically associated with a malignant melanoma. DNA flow cytometry was performed on adjacent cryostat sections of 37 biopsies from 28 CMN without melanoma. PAMAs were found expressed in CMN in the following frequencies: A-1-43: 36%; P358: 27%; PAL-M1: 20%; HLA-DR: 9%; Muc 18: 2%; A-10-33: 0%. No PAMAs were present in only 15 biopsies (34%). One single PAMA was found in 20 lesions (45%), and two or more PAMAs in nine lesions (21%). In all four CMN histologically associated with melanoma, and also in one biopsy from the giant CMN which later progressed to melanoma, at least two PAMAs were expressed. The latter biopsy was the only CMN in which the proliferation-associated antigen could be demonstrated. Only this biopsy and a single biopsy of the other giant CMN showed aneuploidy. We found expression of single PAMAs and co-expression of PAMAs in CMN in higher frequency than in common acquired melanocytic nevi. Co-expression of PAMAs was a feature of metastasizing primary melanomas. We conclude that co-expression of two or more PAMAs in a CMN might indicate its malignant potential, because this was found in all CMN proven to have progressed to malignant melanoma.