We have analysed 47 early-onset (< or =40 years) Latvian melanoma patients for the involvement of the melanoma susceptibility loci CDKN2A and CDK4. We observed no disease-related mutations in CDKN2A, but one patient had a CDK4 R24H mutation and strong family history of melanoma. Haplotype analysis using microsatellite markers and single nucleotide polymorphisms showed that the Latvian haplotype is unique compared with that of other melanoma families with the R24H mutation. This finding supports the proposal that codon 24 is a mutational hotspot in the CDK4 gene.