BACKGROUND Breslow thickness, ulceration, and sentinel lymph node (SLN) status are well established as the most important prognostic factors for patients with cutaneous melanoma. Anatomic location of the primary tumor is generally considered to play a minor role in determining prognosis compared with these other factors. This analysis was performed to better define the influence of anatomic location of the primary melanoma on prognosis. METHODS In this post hoc analysis of a prospective randomized trial that included patients ages 18 to 70 years with melanomas 1 mm or greater in Breslow thickness, all patients underwent SLN biopsy and completion lymphadenectomy if tumor-positive SLN were found. Kaplan-Meier survival analysis and univariate and multivariate analyses were performed to evaluate factors predictive of disease-free survival (DFS), local and in-transit recurrence-free survival (LITRFS), and overall survival (OS). RESULTS A total of 2,500 patients were included in this analysis with a median follow-up period of 68 months. Anatomic locations included head, neck, trunk, upper extremity, and lower extremity. Age, Breslow thickness, and percentage of patients with a positive SLN were significantly different by anatomic location on univariate analysis, as were positive SLN status, presence of regression, sex, and histologic subtype (P < .0001). On multivariate analysis, anatomic location was an independent predictor of SLN status (P < .0001), DFS (P = .045), LITRFS (P = .023), and OS (P < .0001). By Kaplan-Meier analysis, anatomic location was associated significantly with DFS, LITRFS, and OS. CONCLUSIONS Anatomic location of the primary melanoma is an important independent predictor of SLN status and prognosis. Patients with primary melanomas of the head/neck and trunk have a worse prognosis than primary melanomas of other anatomic locations.