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Summary: Background: Germline mutations in telomere‐related genes such as POT1 and TERT predispose individuals to familial melanoma. Objectives: To evaluate the prevalence of germline mutations in POT1 and TERT in a large cohort of Spanish melanoma‐prone families (at least two affected first‐ or second‐degree relatives). Methods: Overall, 228 CDKN2A wild‐type melanoma‐prone families were included in the study. Screening of POT1 was performed in one affected person from each family and TERT was sequenced in one affected patient from 202 families (26 families were excluded owing to DNA exhaustion/degradation). TERT promoter sequencing was extended to an additional 30 families with CDKN2A mutation and 70 patients with sporadic multiple primary melanoma (MPM) with a family history of other cancers. Results: We identified four families with potentially pathogenic POT1 germline mutations: a missense variant c.233T>C (p.Ile78Thr); a nonsense variant c.1030G>T (p.Glu344*); and two other variants, c.255G>A (r.125_255del) and c.1792G>A (r.1791_1792insAGTA, p.Asp598Serfs*22), which we confirmed disrupted POT1 mRNA splicing. A TERT promoter variant of unknown significance (c.‐125C>A) was detected in a patient with MPM, but no germline mutations were detected in TERT promoter in cases of familial melanoma. Conclusions: Overall, 1·7% of our CDKN2A/CDK4‐wild type Spanish melanoma‐prone families carry probably damaging mutations in POT1. The frequency of TERT promoter germline mutations in families with melanoma in our population is extremely rare. What's already known about this topic? Germline mutations in telomere‐related genes predispose to familial melanoma.The prevalence of germline mutations in telomere‐related genes has not been widely studied in melanoma families of Iberian descent. What does this study add? This study evaluates for the first time the prevalence of POT1 and TERT promoter mutations in a hospital‐based series of 228 CDKN2A‐negative families with melanoma from Barcelona, Spain.We identified POT1, but no TERT promoter, mutations in 1·7% of families.The results will facilitate genetic counselling and screening of families with melanoma. What is the translational message? Analysis of telomere‐related genes showed rare POT1 variants in a subset of Spanish melanoma‐prone families, while mutations in the TERT promoter were extremely rare.If extended to additional families and cancer types, these findings may have important implications for genetic counselling. Linked Comment: Toland. Br J Dermatol 2019; 181:14–15. Plain language summary available online Respond to this article [ABSTRACT FROM AUTHOR]