Background: Cutaneous melanoma (CM) management depends on an estimate of recurrence risk or death. Because of recognized disease risk and drug efficacy, pembrolizumab immunotherapy has been approved for stage IIB-C patients. However, it is a treatment with potential financial and biological toxicities with 16% of patients experiencing severe treatment related adverse events. Improved risk stratification could identify individuals for whom more selective management would be appropriate. In collaboration with the NCI Surveillance, Epidemiology, and End Results (SEER) program, which includes information on patients tested with a 31-gene expression profile (31-GEP) test in an unbiased and unselected manner, we confirm the 31-GEP adds independent prognostic value in patients with stage I-III CM, and investigated whether the 31-GEP could identify stage IIB-C patients who might reasonably avoid adjuvant therapy while also identifying patients with stage I disease who might benefit from more aggressive diagnostic and/or therapeutic intervention. Methods: SEER registries linked CM cases diagnosed 2013-2018 to 31-GEP test results provided by Castle Biosciences (9,207 matched) using a registry trusted third party (honest broker), including subsets of stage IIB-IIC (n=775) and stage I (n=5,651) melanoma. The primary endpoint was melanoma-specific survival (MSS). The 31-GEP risk-groups included Class 1A (low), Classes 1B/2A (intermediate), and Class 2B (high). Each was compared using Kaplan-Meier analysis and the log-rank test. Results: In the overall cohort, patients with a Class 1A result had a significantly higher 5-year MSS than a Class 1B/2A or Class 2B result (97.4% vs. 93.5% vs. 83.3%, p<0.001). In multivariable analysis, a Class 2B result (HR=3.26, p<0.001) and positive lymph node status (HR=3.41, p<0.001) were the strongest predictors of diminished MSS. In stage IIB-C, 18.8% (146/775) of patients received a Class 1A result with an associated 5-year MSS of 89.1% (vs. Class 2B: 76.6%, p=0.001), despite the absence of pembrolizumab approval for the evaluated SEER population. Alternatively, 4.6% (260/5,651) of patients with stage I disease had a Class 2B result, with an associated 5-year MSS of 92.3% (vs. Class 1A: 98.0%, p<0.001). Conclusions: The SEER database allowed a non-biased analysis of a large cohort of patients with stage I-III CM who were tested with the 31-GEP. The 31-GEP identifies patients, including those with stage IIB-C disease, with favorable outcomes and could help physicians and patients decide whether to pursue adjuvant therapy. Moreover, the 31-GEP identities high-risk patients, including those with stage I disease, for whom more aggressive follow-up and early intervention should be considered.