Melanoma is an immunogenic tumor; however, the efficacy of immune-therapy shows large inter-individual variation with possible influence of background genetic variation. In this study we report the influence of genetic polymorphisms in the type I interferon gene cluster on chromosome 9p22 on melanoma survival. We genotyped 625 melanoma patients recruited in an oncology center in Germany for 44 polymorphisms located on chromosome 9p22 that were informative for 299 polymorphisms and spanned 15 type I interferon genes. Our results showed associations between time to metastasis/survival and two linked (r(2) = 0.76) polymorphisms, rs10964859 (C>G) and rs10964862 (C>A). The rs10964859 polymorphism was located at 3'UTR and rs10964862 was 9.40 Kb towards 5'UTR of IFNW1 gene. The carriers of the variant alleles of the rs10964859 and rs10964862 polymorphisms were associated with a reduced disease-free survival. The validation of data in an independent group of 710 patients from Spain showed that the direction of the effect was similar. Stratification based on therapy showed that the adverse effect on metastasis development was statistically significant in the patients from Spain who did not receive any treatment and were homozygous for variant allele of rs10964862 (HR = 2.52, 95% CI 1.07-5.90; P = 0.03). Patients homozygous for rs10964859 (HR = 2.01, 95% CI 1.17-3.44; P = 0.01) and rs10964862 (HR 1.84, 95%CI 1.03-3.27, P = 0.04) were associated to increased risk of death following metastasis. GTCGACAA haplotype, found in 8.8% of the patients, was associated with an increased risk of death (HR 1.94, 95%CI 1.16-3.26, P = 0.01). In conclusion, our results identified genetic variants in interferon genes that influence melanoma progression and survival with modulation of effect due to treatment status.