Introduction: Some melanoma patients who undergo sentinel lymph node (SLN) biopsy will have false-negative (FN) results. We sought to determine the factors and outcomes associated with FN SLN biopsy. Methods: Analysis was performed of a prospective multi-institutional study that included patients with melanoma of thickness > 1.0 mm who underwent SLN biopsy. FN results were defined as the proportion of node-positive patients who had a tumor-negative sentinel node biopsy. Kaplan-Meier survival analysis and univariate and multivariate analyses were performed. Results: This analysis included 2,451 patients with median follow-up of 61 months. FN, true-positive (TP), and true-negative (TN) SLN results were found in 59 (10.8%), 486 (19.8%), and 1,906 (77.8%) patients, respectively. On univariate analysis comparing the FN with TP groups, respectively, the following factors were significantly different: age (52.6 vs. 47.6 years, p = 0.004), thickness (mean 2.1 vs. 3.1 mm, p = 0.003), lymphovascular invasion (LVI; 3.7 vs. 13.7%, p = 0.037), and local/in-transit recurrence (LITR; 32.2 vs. 12.4%, p < 0.0001); these factors remained significant on multivariate analysis. Overall 5-year survival was greater in the TN group (86.7%) compared with the TP (62.3%) and FN (51.3%) groups (p < 0.0001); however, there was no significant difference in overall survival comparing the TP and FN groups (p = 0.32). Conclusions: This is the largest study to evaluate FN SLN results in melanoma, with a FN rate of 10.8%. FN results are associated with greater patient age, lower mean thickness, less frequent LVI, and greater risk of LITR. However, survival of patients with FN SLN is not statistically worse than that of patients with TP SLN. © 2009 Society of Surgical Oncology.