BACKGROUND: The prognostic role Ki-67, p53, and p16 immunostains and RET (rearranged during transfection) polymorphism in desmoplastic melanoma has not been evaluated. OBJECTIVE: We sought to identify potential prognostic markers. METHODS: We performed Ki-67, p53, and p16 immunostains on 66 desmoplastic melanomas, and sequenced RET G691 polymorphism and recurrent mutations of 17 cancer genes in 55 and 20 cases, respectively. RESULTS: Recurrence and metastasis were documented in 11 of 66 (17%) and 26 of 66 (39%) patients, respectively. Death was noted in 25 of 55 (45%) patients. Ki-67 expression (≥10%, 43%) correlated with male gender (P = .009), ulceration (P = .002), and Breslow depth (P = .009). p53 Expression (≥50%, 28%) correlated with male gender (P = .002) and head and neck location (P = .0228). Using Kaplan-Meier plots, Ki-67 expression (P = .0425) and mitosis (P = .00295) correlated with overall survival, whereas vascular invasion (P = .0292) correlated with disease progression. There was a significant correlation between Ki-67 and p53 expression (P = .003). RET polymorphism was present in 10 of 46 (22%) cases and inversely correlated with Breslow depth (P = .024). LIMITATION: Our study is small and lacks power to perform a multivariate analysis. CONCLUSION: Although Ki-67 expression correlated with overall survival, additional studies are needed to determine whether Ki-67 would be an independent prognostic marker in addition to the current routine histopathologic assessment.