To determine how results from a prognostic 40-gene expression profiling (40-GEP) test would impact clinician management decisions and how their choices would align with a National Comprehensive Cancer Network (NCCN) compliant, risk-directed management plan for high-risk cutaneous squamous cell carcinoma (cSCC). Clinicians attending a national dermatology conference were presented with 40-GEP test validation data. They were asked to rate clinicopathological features and molecular test results to assess their opinion of how concerning each is to cSCC prognosis. When presented with vignettes describing patients with NCCN-defined high-risk features, clinicians were asked to select a treatment plan using pre-test (no 40-GEP results), then, post-test (40-GEP Class 1, 2A, or 2B results) methodology along with corresponding metastasis rates for each test group. Risk factors deemed of highest concern for metastatic outcomes were a Class 2B 40-GEP result, perineural invasion, immunosuppression, invasion beyond subcutaneous fat, and tumor diameter >1 cm on the scalp. When presented with a 40-GEP result that indicated reduced risk of metastasis (Class 1), clinicians altered their treatment management plan accordingly. Specifically, there was significant reduction in the recommendations for sentinel lymph node biopsy, adjuvant radiation or chemotherapy, follow-up time, and nodal imaging. By comparison, when a 40-GEP result indicated an increased risk of metastasis (Class 2B), significant risk-appropriate increases in management intensity was observed for the aforementioned clinical decisions. Integration of 40-GEP results impacted management decisions in a significant and risk-appropriate manner for high-risk cSCC patient scenarios, while remaining aligned with national guidelines for patient management.