Hypothesis: The number of nodal basins draining a primary cutaneous melanoma is not an independent predictor of outcome. Design: Post hoc analysis of patients entered into a randomized, prospective study. Setting: Multi-institutional academic and community medical centers. Patients: Patients aged 18 to 70 years with melanoma 1.0 mm or greater Breslow thickness. Interventions: Wide local excision and sentinel lymph node biopsy were performed on all patients; patients with sentinel lymph node metastases underwent completion lymphadenectomy. Patients with multiple-nodal basin drainage were compared with those with single-nodal basin drainage. Main Outcome Measures: Sentinel lymph node status, locoregional recurrence-free survival, disease-free survival, and overall survival. Results: A total of 2060 patients with single-nodal basin drainage (n=1709 [83% of cohort]) were included in the analysis, with a median follow-up of 50 months. On univariate analysis, the group with multiple-nodal basin drainage (n=351) was associated with female sex and primary tumor regression (P<.001). In addition, multiple-nodal basin drainage was associated with truncal primary tumor location (73.2%), while single-nodal basin drainage was more common for extremity tumors (50.9%; P<.001). On multivariate analysis, there were no differences in the rate of sentinel lymph node metastasis, disease-free survival, or overall survival between the groups. Interestingly, locoregional recurrence was significantly worse in the single-nodal basin drainage group (P=.003). Conclusions: Multiple-nodal basin drainage does not confer a worse prognosis for patients with cutaneous melanoma. In fact, single-nodal basin drainage appears to be associated with a greater risk of locoregional recurrence. ©2008 American Medical Association. All rights reserved.