Background The Clinicopathological and Gene Expression Profile (CP-GEP) model was developed to accurately identify patients with T1-T3 primary cutaneous melanoma at low risk for nodal metastasis. Objectives To validate the CP-GEP model in an independent Dutch cohort of patients with melanoma. Methods Patients (aged ≥ 18 years) with primary cutaneous melanoma who underwent sentinel lymph node biopsy (SLNB) between 2007 and 2017 at the Erasmus Medical Centre Cancer Institute were eligible. The CP-GEP model combines clinicopathological features (age and Breslow thickness) with the expression of eight target genes involved in melanoma metastasis (ITGB3, PLAT, SERPINE2, GDF15, TGFBR1, LOXL4, CXCL8 and MLANA). Using the pathology result of SLNB as the gold standard, performance measures of the CP-GEP model were calculated, resulting in CP-GEP high risk or low risk for nodal metastasis. Results In total, 210 patients were included in the study. Most patients presented with T2 (n = 94, 45%) or T3 (n = 70, 33%) melanoma. Of all patients, 27% (n = 56) had a positive SLNB, with nodal metastasis in 0%, 30%, 54% and 16% of patients with T1, T2, T3 and T4 melanoma, respectively. Overall, the CP-GEP model had a negative predictive value (NPV) of 90Á5% [95% confidence interval (CI) 77Á9-96.2], with an NPV of 100% (95% CI 72Á2-100) in T1, 89Á3% (95% CI 72Á8-96Á3) in T2 and 75Á0% (95% CI 30Á1-95Á4) in T3 melanomas. The CP-GEP indicated high risk in all T4 melanomas. Conclusions The CP-GEP model is a noninvasive and validated tool that accurately identified patients with primary cutaneous melanoma at low risk for nodal metastasis. In this validation cohort, the CP-GEP model has shown the potential to reduce SLNB procedures in patients with melanoma.What is already known about this topic?• The majority (70-85%) of patients with cutaneous melanoma who undergo a sentinel lymph node biopsy (SLNB) procedure have no metastasis in the SLN.• To identify patients at low risk for nodal metastasis, the Clinicopathological and Gene Expression Profile (CP-GEP) model was developed (n = 754 patients, US cohort).• The CP-GEP model combines age, Breslow thickness and the expression of eight target genes involved in melanoma metastasis, and has the potential to reduce SLNB procedures in patients with T1-T3 cutaneous melanoma.