Abstract: Several germline mutations and sequence variants in cancer predisposition genes have been described. Among these, the CDKN2A p.A148T variant appears to be frequent in patients with melanoma, at least in certain ethnic groups. In this case–control study, we evaluated 127 patients with cutaneous melanoma and 128 controls from Southern Brazil, the region with the highest melanoma incidence rates in the country. Using PCR–RFLP, we demonstrate that CDKN2A p.A148T variant was significantly more frequent in patients with melanoma than in controls (12.6% vs 3.9%; P = 0.009). There was no association between presence of the polymorphism and tumor thickness, site of the primary tumor, melanoma subtype, age at diagnosis, quantitative and qualitative number of nevi. Patients with a positive family of history for other cancers were particularly prone to carry the CDKN2A p.A148T allele. All patients with p.A148T-positive melanoma reported European ancestry, especially German, and this was confirmed using a panel of ancestry-informative INDELs. Our data suggest that CDKN2A p.A148T is a melanoma susceptibility allele in Southern Brazil and is particularly common in patients with melanoma of predominantly European ancestry.