BACKGROUND Differentiating benign blue nevi from blue nevus-like melanoma can be diagnostically challenging. We aimed to determine the utility of immunohistochemical staining for p16 and cyclin D1 in distinguishing benign blue nevi and malignant melanoma. MATERIALS AND METHODS Thirty-two biopsy specimens taken between 2007 and 2015 were obtained from the Department of Pathology at the Queen's Medical Center in Honolulu, HI. These included 9 common blue nevi, 8 cellular blue nevi (2 with atypical features), and 15 malignant melanomas (3 blue nevus-like melanoma). The primary outcome was the difference in p16 and cyclin D1 staining between benign blue nevi and malignant melanoma. Staining of specimens for p16 and cyclin D1 was graded on the strength of staining, and the percent of tumor that stained positive. A specimen was deemed positive if it showed 2+ staining in ≥50% of the tumor. RESULTS The majority (82%) of blue nevi stained negative for p16. There was not a significant difference between p16 staining in benign blue nevi and melanoma (P=0.06). Eleven (73%) melanomas stained positive for cyclin D1 with a sensitivity of 0.73 and positive predictive value of 1.0. All blue nevi were negative for cyclin D1, making its specificity 1.0 and its negative predictive value 0.8. This difference in cyclin D1 staining in blue nevi and melanoma was significant (P=0.0001). CONCLUSIONS Cyclin D1 may be useful in differentiating benign blue nevi from melanoma.