Chromosome 9p21 contains a susceptibility gene for cutaneous melanoma. Recent studies suggest that the gene responsible may be CDK41, since it encodes a putative cell cycle inhibitor, p16, and is frequently lost or rearranged in melanoma cell lines. In this study we examined whether germline alterations in CDK41 could be identified in patients with melanoma of the uveal tract. From an archive of bloods collected from patients with uveal melanoma, we identified 13 samples drawn from patients with a history in a family member of uveal (n = 6) or cutaneous (n = 7) melanoma. An additional 24 'control' bloods (without melanoma or any other primary malignancy in a family member), similar to the 'cases' in age and number of first-degree relatives, were also selected for study. For each sample, DNA was extracted from the red blood cell fraction. Using the polymerase chain reaction-single strand conformation polymorphism method, we screened for alterations in p16. Specific changes were characterized by DNA sequencing. Six nucleotide changes were detected in five (13.5%) of the 37 samples examined. An altered gene was found in one (7.7%) of the 13 patients with a family history (of intra-ocular melanoma) and four (16.7%) of the 24 patients with no family history (P = 0.64) of melanoma. In this series the group with a positive family history was predominantly female and most pedigrees involved matrilineal descent. In these data prevalence of germline alteration in p16 was similar in familial and sporadic cases. The results provide evidence against a significant role for p16 in familial clustering of intra-ocular and cutaneous melanomas.