Malignant melanoma occurs as a familial cancer in 5%-10% of cases, where it segregates in a manner consistent with autosomal dominant inheritance. Evidence from cytogenetics, fine mapping studies of deletions in melanomas and recent linkage studies supports the location of a human melanoma predisposition gene on the short arm of chromosome 9. Evidence also exists for a melanoma gene on Ip, indicating genetic heterogeneity for melanoma predisposition. Previous studies have also reported findings suggestive of linkage of some melanoma families to the HLA region on the short arm of chromosome 6 (6p), indicating the possibility of even greater heterogeneity. To further define the possible effect of a gene within the HLA region on melanoma susceptibility, we have typed 7 simple tandem repeat polymorphisms (STRPs) from 6p in 16 Australian melanoma kindreds. Maximum 2-point LOD scores ranged from 1.13 (theta = 0.2) to 2.03 (theta = 0.15) for 4 contiguous markers flanking the HLA complex, and multi-point analysis gave a peak LOD score of 1.64, 24 centimorgans telomeric to D6S109. However, extended haplotype analysis of these markers showed that a region between D6S105 and HLAF segregated with melanoma in 5/16 families. These results are surprising given that the same cohort of families has previously been shown to be linked to chromosome 9. One interpretation of the current findings is that melanoma susceptibility in some families may result from a gene mapping within the HLA region of chromosome 6p.