Proliferative neoplasms that resemble malignant melanoma may develop in large congenital melanocytic nevi, prenatally or in the neonatal period, although these lesions rarely show the progressive growth or behavioral characteristics of melanoma. This report describes the genetic, biologic, and immunologic characteristics of six tissue culture cell lines derived from two neoplasms present in congenital melanocytic nevi in two newborn infants. Both neoplasms had clinical and histologic features of malignant melanoma. Despite these features, cells from all lines were phenotypically benign, as evidenced by a normal karyotype, their expression pattern of pigment cell-associated antigens, absence of melanoma-associated ganglioside GD2, their mitogenic response to the tumor-promoting phorbol ester 12-0-tetradecanoyl phorbol-13-myristate, their inability to grow anchorage independently in soft agar, and prolonged but finite life span. The cells did not produce tumors in nude mice, but they remained viable at the injection site for over 7 months.