Histological evaluation of epidermal melanocytes on routine staining is difficult and cannot be made with accuracy. Widely known antibodies such as S-100 and HMB-45 are unreliable for normal epidermal melanocytes. Furthermore, S-100 stains other cells including Langerhans' cells. Results of incubation with DOPA are inconsistent and the procedure is time-consuming. We have evaluated the use of Mel-5, an antibody that was developed against melanoma and melanocytes. This antibody is a mouse monoclonal antibody that specifically detects a 75 kDa glycoprotein usually expressed by normal melanocytes, naevi and melanoma cells in routinely fixed paraffin sections. Histological differentiation between pigmented actinic keratosis in photodamaged skin and lentigo maligna can be difficult. The atypical keratinocytes, particularly in the basal layer, can be confused with atypical melanocytes, especially if they are pigmented. Similarly, distinctions between lichen planus-like keratosis and lichenoid melanoma in situ and lentigo maligna and lentigo may be difficult. Use of Mel-5 in such cases has shown consistent results in separating melanocytic from non-melanocytic lesions. This antibody is also helpful in evaluating biopsies of patients with vitiligo, post-inflammatory pigmentary alteration and regressed or regressing melanocytic lesions. Furthermore, Mel-5 is an invaluable tool in quantification of epidermal melanocytes in research projects.