Nevus cell components have been observed in up to 40% of melanomas, but little is known of the pathobiology of these components in relation to their malignant potential. We studied 44 nevi of the typical, dysplastic, congenital, and Spitz types with a battery of monoclonal and polyclonal antibodies that react on formalin-fixed, paraffin-embedded tissues (HMB.45, S-100 protein, RAP-5, epithelial membrane antigen [EMA], and neuron-specific enolase [NSE]) by avidin-biotin immunohistochemical methods. EMA and RAP-5 (which detects the ras oncogene-associated P21 protein) were negative in all cases. Melanoma-specific HMB.45 was strongly reactive with the epidermal component and had a weak to negative reaction with the dermal component in the typical nevi. However, the reaction seen with HMB.45 in the junctional component of dysplastic nevi, congenital nevi, and some Spitz nevi was heterogeneous. One Spitz nevi showed HMB.45 staining in a pattern near to that of melanoma. In contrast to HMB.45, S-100 protein labeled nevomelanocytes, regardless of whether they were within the epidermis or dermis, although, in half of the dysplastic nevi, the reaction was heterogeneous, with some atypical cells failing to stain. But, with cytologically atypical junctional component (dysplastic-appearing), congenital nevi also stained heterogeneously for S-100 protein compared with the dermal component. NSE stained the central component of some Spitz nevi more intensely than the lateral component. Junctional nevomelanocytic subsets of some congenital nevi revealed HMB.45 and S-100 reactivity similar to dysplastic nevi.