Background: We recently validated a GEP test that provides accurate prediction of metastatic risk for CM cases. The GEP of 31 genes provides a binary outcome of Class 1 (low risk of metastasis) or Class 2 (high risk). This study evaluated the prognostic. Methods: Of 406 patients with successful GEP results and clinical data, 217 had a documented SLNB. All samples and clinical data were collected under an IRB approved, multicenter protocol. Quantitative PCR analysis was performed to assess expression of the gene signature, and Radial Basis Machine predictive modeling was used to determine risk prediction (Class 1 vs. Class 2). Results: SLNB+ status (n=58) was associated with greater median Breslow thickness, increased mitotic rate, and ulceration. Metastasis was reported for 37 of 58 (64%) SLN+ cases and 70 of 159 (44%) SLN- cases. While positive predictive values for Class 2 and SLN+ status were comparable (69% vs. 64%, resp.), negative predictive values of 75% and 49% were observed for low risk Class 1 and SLN- cases, respectively. Kaplan-Meier (K-M) analysis revealed 5-year MFS of 34% and 37%, respectively, for GEP Class 2 and SLN+ cases, and OS of 54% and 62% for the two groups, respectively. K-M analysis of MFS and OS for GEP and SLN in combination resulted in outcomes shown in Table 1. Cox multivariate analysis showed that GEP Class 2 and positive SLN status were significant predictors of MFS (HR=4.9 and 1.7, resp., p<0.01), but that GEP, in this group of patients, was the only significant predictor of OS (HR=5.1, p<0.0001). Conclusions: In this study cohort, GEP provided an objective, non-invasive tool that accurately predicted MFS and OS in SLN eligible patients. Importantly, in the discordant Class 2/SLN- group, predicted outcomes more closely reflected Class 2 status. Incorporation of GEP class in treatment planning may enable improved patient management. MFS and OS association with class and SLN status.