In epithelial-lined organs, severe dysplasia equates with carcinoma in situ. In melanocytic lesions, some authors and pathologists distinguish severe dysplasia from melanoma in situ. Treatment strategies and prognostic implications differ for these lesions. While histologic features are useful in differentiating these neoplasms, this study evaluated PRAME immunohistochemistry in severely dysplastic nevus and melanoma in situ to determine if this new immunohistochemical marker is helpful in this context. Results showed that melanoma in situ and severely dysplastic nevus differ with regard to PRAME immunoreactivity which can help distinguish these lesions along with histologic features. While larger samples and prospective follow-up are ideal, it appears that use of PRAME immunohistochemistry will help pathologists differentiate these two lesions and ensure dermatologists treat each appropriately.