Background: Accurate interpretation of frozen sections in the treatment of melanoma by Mohs micrographic surgery may be difficult. Objective: Our purpose was to review the literature on the role of Mohs micrographic surgery in the treatment of melanoma and to demonstrate the added benefits of using rapid HMB-45 staining in Mohs micrographic surgery for the treatment of melanoma. Methods: Twenty cases of melanoma were included in our study. Histologic diagnosis in each case was made by means of excisional biopsy specimens and permanent sections. Mohs micrographic surgery was performed with 3-mm margins used for each stage. Each Mohs frozen section was stained with HMB-45. In addition, routine frozen sections stained with hematoxylin-eosin were also prepared for comparison. All tissues were also sent for permanent sections. These permanent sections were cut similarly to Mohs-oriented sections because they were sectioned horizontally. Since they were serving as the standard, no staining with HMB-45 was performed on these permanent sections. Further stages with 3-mm margins were taken until tissues stained negative. Frozen sections were compared with permanent sections at each stage of resection. Results: Eleven of the 20 cases stained positive with HMB-45 antibody on the first Mohs stage. These results were consistent with findings on permanent sections. Ten of the 11 cases were cleared by the first stage. One of the 11 cases required 3 stages because margins were not cleared and the specimens stained HMB-45 positive. However, permanent sections in this case revealed no tumor in the second stage. Nine of 20 cases did not stain with HMB-45 on the first layer of Mohs excision. This was consistent with findings on permanent sections. Conclusion: HMB-45 staining serves as a rapid technique to aid in the interpretation of frozen sections during Mohs micrographic surgery in the treatment of melanoma. (J Am Acad Dermatol 2001;44:833-6.)