Acute, low-dose ultraviolet B radiation protocols impair induction of contact hypersensitivity (CHS) to highly reactive haptens in some mice and humans (UVB-susceptible) but not others (UVB-resistant). These deleterious effects of ultraviolet radiation appear to be mediated in part by tumour necrosis factor alpha (TNF-alpha), which is released from, or accumulates in, UVB-exposed skin. To test the hypothesis that a polymorphism of the Tnfa locus governs the UVB-S and UVB-R phenotypes, studies have been conducted in genetically disparate strains of mice. Mice carrying the Tnf(d) allele [with precisely 14 (CA) repeats in the promoter region] display the UVB-R phenotype, whereas mice with different Tnf alleles [with (CA) repeats of </>14] display the UVB-S phenotype. Molecular genetic studies of the TNF region of HLA in humans displaying either the UVB-S or UVB-R phenotype reveal a significant increase in the frequencies of TNFa2 in UVB-S individuals (P=0.00032) and of TNFd3 in UVB-R individuals (P=0.012). Moreover, DNA sequencing analyses of five single-nucleotide polymorphisms (SNPs) of the TNF promoter region revealed a significant increase in the frequency of TNF/-863A (P=0.015). We propose that the TNF region dictates susceptibility to the deleterious effects of UVB radiation on the induction of contact hypersensitivity in both mice and humans, and that the UVB-S-promoting polymorphisms significantly promote the risk of sunlight-induced skin cancer in humans.