Background: A discrimination between benign and malignant melanocytic lesions is not always possible by conventional histology. Objective: Our purpose was to determine the proliferative activity in various types of melanocytic neoplasms and to appraise its value as a diagnostic adjunct. Methods: The growth fraction was assessed immunohistochemically in 398 melanocytic lesions by means of the monoclonal antibody Ki-S5 directed to the Ki-67 antigen. In this way, a cut-off level was defined and applied to 112 lesions of equivocal histology. The revised diagnoses were correlated to the clinical courses. Results: Common nevi, Spitz nevi, and melanomas exhibited significantly different proliferation indices and distinctive distribution patterns of cycling cells. In agreement, malignancy diagnosed on the basis of a growth fraction greater than 5% was confirmed by disease progression in 68% of our cases with uncertain diagnosis. Conclusion: Determination of the proliferative activity in melanocytic lesions may usefully complement conventional histology to improve diagnostic accuracy. (J Am Acad Dermatol 1997;37:169-78.)