Abstract: The histologic assessment of intraepidermal melanocytic proliferations involving sun-damaged skin may be challenging in scant biopsy material. Melanoma in situ may occasionally be confused with intraepidermal melanocytic hyperplasia on sun-damaged skin; thus, dermatopathologists may use immunohistochemical studies to help distinguish these entities. Historically, melanoma antigen recognized by T-cells 1 (MART-1) has been regarded as a valuable stain to confirm intraepidermal melanocytes; however, MART-1 may overestimate the number of melanocytes because it labels the melanoma dendrites and might also label pigmented keratinocytes, including structures mimicking junctional melanocytic nests in the setting of a lichenoid infiltrate. A total of 70 cases were retrospectively chosen, including 50 cases of melanoma in situ and 20 cases of actinic keratoses. SOX10 and microphthalmia transcription factor 1 (MITF-1) were performed in all cases. In all cases, the number of cells within epidermis that were identified as melanocytes by immunohistochemistry was compared with the number of melanocytes observed by morphology on hematoxylin and eosin sections. All cases of melanoma in situ showed expression of SOX10; however, the proportion of atypical melanocytes showing strong nuclear positivity was variable and did not approach that seen in MITF-1. There was no expression of either MITF-1 or SOX10 in adjacent pigmented keratinocytes in the cases of actinic keratoses. Both MITF-1 and SOX10 can be used to differentiate melanoma in situ from actinic keratosis with melanocytic hyperplasia; however, MITF-1 exhibits slight superior sensitivity and seems to be a more effective immunostain than SOX10 for the identification and quantification of melanocytes in the setting of melanoma in situ, especially in cases where there is limited tissue.