We studied the staining pattern of HMB-45 antibody in 29 compound Spitz nevi (SNs) of the epithelioid cell variety, 17 of which showed extension of nevus cells into the reticular dermis (i.e., “deep”); 20 ordinary compound nevi (CNs), all with a deep dermal component; and 22 primary cutaneous invasive malignant melanomas (MMs) (excluding the desmoplastic and spindle cell types), 12 of which extended into Clark level IV or V. Of the 29 SNs, eight (28%) stained negatively; five (17%), including two deep SNs, stained in the epidermal component only; and 16 (55%), including 10 deep SNs, stained in both the epidermal and dermal components. Of the latter 10 deep SNs, eight stained in the upper dermis only, and in the remaining two lesions, a smaller number of positively stained nevus cells were detectable in the lower dermis as well; these two SNs were not atypical histologically. Of the 20 CNs, four (20%) stained negatively, two (10%) stained in the epidermal component only, and 14 (70%) stained in the epidermal component and the upper dermis only. Of the 22 MMs, one stained negatively, and 21 (95%) stained positively in both the epidermal and dermal components. The pattern was variable in frequency of both staining and distribution, but showed no stratification. We conclude that the majority of our positively stained deep compound SNs showed a stratified pattern of HMB-45 staining, similar to ordinary CNs and different from MMs, and that this pattern might be used as an adjunct in the histopathologic differential diagnosis of compound SN and MM, in the proper clinicopathological context.