This analysis was performed to compare differences in clinicopathologic factors, sentinel lymph node (SLN) status, and survival between upper extremity (UE) and lower extremity (LE) melanoma patients. Post hoc analysis of a prospective clinical trial was performed of all patients with extremity melanomas with complete data. Survival was evaluated with Kaplan-Meier analysis. Univariate and multivariate analyses were performed. A total of 1115 patients aged 18 to 70 years with extremity melanomas ≥ 1.0 mm Breslow thickness were analyzed; all underwent SLN biopsy with completion lymphadenectomy for a tumor-positive SLN. Compared with UE patients, LE melanoma patients were younger, predominantly female, and had a higher rate of SLN metastasis. Kaplan-Meier analysis revealed worse 5-year disease-free survival (DFS) and worse local and in-transit recurrence-free survival in LE versus UE melanoma patients, but no difference in overall survival (OS). Subgroup analysis revealed that older patients (age > 51 years) with LE melanomas had worse DFS, local and in-transit recurrence-free-survival, and OS. LE tumor location was not an independent risk factor for OS or DFS. Compared with UE melanoma patients, those with LE melanomas have a greater risk of tumor-positive SLN and local/in-transit recurrence.