Background: Nowadays, immunotherapy targeting immune checkpoint receptors is one of the cornerstones of systemic treatment in melanoma. Homologous recombination repair (HRR) was a pathway of the DNA damage response (DDR), has been shown to be associated with the efficacy of platinum-based chemotherapy, PARP inhibitor therapy and immunotherapy in variety of cancers. However, their predictive value of HRR remained unknown in patients with advanced melanoma. Methods: An independent cohort (Samstein2018) with data from 99 patients with advanced melanoma were used to analyze the correlation with immunogenic marker the prognostic effect of HRR on immunotherapy, and another four cohorts (Miao2018, Allen 2015, Hugo2016, and Synder2014) are used for validation. Immune filtration cells scores analyzed by the TCGA-SKCM cohort were used to explore potential mechanisms related to the immune microenvironment. Results: Compared to patients with HRR pathway wild-type (HRRwt), those with HRR mutations (HRRmut) in an independent anti-CTLA-4-treated cohort had higher tumor mutation burden (TMB; median: 29.55Muts/Mb versus 4.46Muts/Mb; P = 0.0003), objective response rates (ORR; P = 0.007), and longer overall survival (OS; median: 58 versus 22 months, hazard ratio (HR) = 2.4, 95%CI 1.17-4.92, P = 0.014). These findings were further validated in a pooled anti-CTLA-4-treated cohort in terms of the ORR and OS. However, there was no correlation between HRRmut and OS in the anti-PD-1-treated cohort. Subgroup analysis showed that although patients with HRRmut received the same benefits from anti-CTLA-4 and anti-PD-1/L1 therapy (p = 0.59), the value of anti-CTLA-4 therapy in the HRRmut group was similar or even better than that in the anti-PD-1/L1 therapy group (24.1 months vs 22.7 months), which unlike it in the HRRwt group (10.8 months vs 32.0 months). In addition, transcriptome profiling analysis revealed that 44 (66.7%) genes mutation of HRR pathway associated with reshaping of the immunological microenvironment in melanoma tumors. Conclusions: HRRmut were associated with a higher TMB level, and immunotherapeutic effect. HRR may serve as an independent predictor of anti-CTLA-4 therapy efficacy in patients with advanced melanoma and their clinical value warrants further investigation.