Background: Acral melanoma is dominant in Asia, which differs from cutaneous melanoma in etiology, mutation loading, and therapy response. Growing evidence indicates that various components of the lipid profile may be associated with cancer clinical outcomes and the disrupted cholesterol homeostasis plays a potential role in melanoma development. Therefore, we examined the prognostic value of the preoperative serum lipid profile in patients with acral melanoma. Methods: This is a retrospective study consisting of 239 patients who underwent radical surgical resection for acral melanoma between 2000 and 2011 at Sun Yat-sen University Cancer Center. Kaplan-Meier survival analysis and Cox proportional model were used to calculate overall survival (OS) and disease-free survival (DFS). Results: Elevated HDL-C levels were significantly associated with longer OS both in univariate (P<0.001) and multivariate (P=0.005) analyses. The median OS of patients with a low HDL-C level was worse than those with a high HDL-C level (38.09 vs. 50.1 months, HR: 2.63). Univariate analyses showed that a shorter DFS was associated with a low HDL-C level (P<0.001) and was still obviously in the multivariate analysis (P=0.043). The median DFS of patients with a low HDL-C level was worse than those with a high HDL-C level (17.26 vs. 30.09 months, HR: 1.739). There was no significant difference in the OS or DFS based on LDL-C, CHO, and TG levels. Conclusion: Preoperative serum HDL-C may serve as a valuable marker to predict the outcomes of acral melanoma patients.