Adjuvant therapies have been approved for patients with AJCC (American Joint Committee on Cancer) stage III and stage IV cutaneous melanoma (CM) after complete resection. These therapies might also be indicated for patients with high-risk stage II CM. We included patients diagnosed with stage II melanoma between 2000 and 2016 and for which primary tumour tissue was available. The prognostic value of the 11-gene expression profiling score (GEPS) was evaluated as a dichotomized parameter (GEPS ≤0 vs. >0). Endpoints of the analysis were melanoma specific survival (MSS), distant metastasis-free survival (DMFS) and relapse-free survival (RFS). GEPS was determined in 245 patients ranging between −0.7 and 3.53. A total of 111 females and 134 males were included; the median follow-up was 41 months. Kaplan Meier analyses showed statistically significant survival differences between patients with high GEPS (n = 154) and low GEPS (n = 91) for MSS (p = 0.018), DMFS (p = 0.005) and RFS (p = 0.009). The 5-year and 10-year MSS was 92% in the low-GEPS and 82% and 67% in the high-GEPS group, respectively. Multivariate Cox regression analysis showed independent significance for MSS of GEPS (HR = 1.55; p = 0.006), tumor thickness (HR = 1.21; p < 0.001) and age (HR1.05; p = 0.002). GEPS was validated as independent prognostic factor for MSS in stage II CM and could be used for therapeutic decisions when systemic therapies become available in stage II CM. •Regardless of the AJCC classification, GEPS distinguishes between patients with favorable and unfavorable prognosis.•Patients with low GEPS showed a 5-and 10-years melanoma specific survival (MSS) rate of 92%.•Patients with a high GEPS had a 5- and 10-years MSS rate of 82% and 67%, respectively.•Systemic adjuvant therapy may be considered for the high GEPS cohort.