Background: Combined immunotherapy has significantly improved survival of patients with advanced melanoma, but there are still patients that do not benefit from it. Early biomarkers that indicate potential resistance would be highly relevant for these patients. Methods: We comprehensively analyzed tumor and blood samples from patients with advanced melanoma, treated with combined immunotherapy and performed descriptive and survival analysis. Results: Fifty-nine patients with a median follow-up of 13 months (inter quartile range (IQR) 11–15) were included. Interestingly, nine patients were found to have pathogenic or likely pathogenic (P/LP) germline variants in one of these genes: BRCA2, POLE, WRN, FANCI, CDKN2A, BAP1, PALB2 and RAD54B. Most of them are involved in DNA repair mechanisms. Patients with P/LP germline variants had a significantly shorter progression-free survival (PFS) and melanoma specific survival (MSS) compared to patients without P/LP germline variants (HR = 2.16; 95% CI: 1.01–4.64; p = 0.048 and HR = 3.21; 95% CI: 1.31–7.87; p = 0.011, respectively). None of the patients with a P/LP germline variant responded to combined immunotherapy. In the multivariate Cox-regression analysis, presence of a P/LP germline variant, S100B and lactate dehydrogenase (LDH) remained independently significant factors for MSS (p = 0.036; p = 0.044 and p = 0.001, respectively). Conclusions: The presence of P/LP germline variants was associated with resistance to combined immunotherapy in our cohort. As genes involved in DNA repair mechanisms are also involved in lymphocyte development and T-cell differentiation, a P/LP germline variant in these genes may preclude an antitumor immune response.