Background: The histologic discrimination of melanoma in situ of sun-damaged skin (MIS) from chronically sun-damaged skin (SDS) can sometimes be difficult using accepted criteria. Objective: We evaluated these entities by means of morphometry and multifactorial analysis. Methods: We measured the number and area of melanocyte nuclei, melanocyte nucleoli, stratum spinosum keratinocyte nuclei, and papillary dermal lymphocyte nuclei from hematoxylin-eosin–stained slides representing 38 cases of MIS and 18 cases of SDS matched for age, sex, and site with a high-resolution digital imaging and analysis system. Results: Multiple logistic regression analysis correctly classified 100% of the cases using the number of melanocytes per 0.5 mm and the maximum melanocyte nuclear area divided by the maximum keratinocyte nuclear area. The strongest results were achieved measuring approximately 1 mm of epidermis. Conclusion: Morphometry and multifactorial analysis can distinguish MIS from SDS. Morphometric analysis of melanocytic proliferations may be useful at the margins of surgical resections. (J Am Acad Dermatol 1998;39:239-45.)