To gain insight into the molecular mechanisms involved in the inherited predisposition to melanoma and associated neural system tumours, 42 Jewish, mainly Ashkenazi, melanoma families with or without neural system tumours were genotyped for germline point mutations and genomic deletions at the CDKN2A/ARF and CDK4 loci. CDKN2A/ARF deletion detection was performed using D9S1748, an intragenic microsatellite marker. Allele dosage at the p14ARF locus was analysed by quantitative real-time PCR employing a TaqMan probe that anneals specifically to exon 1beta of the p14ARF gene. For detecting point mutations, dHPLC and direct sequencing of the coding sequences of CDKN2A/ARF and CDK4 was used. No germline alterations in any of the tested genes were detected among the families under study. We conclude that in the majority of Ashkenazi Jewish families, the genes tested are unlikely to be implicated in the predisposition to melanoma and associated neural system tumours.