Cutaneous malignant melanoma (CMM) is a potentially fatal malignancy in which exposure to UV light is the most important risk factor. Several lines of evidence suggest that increased expression of tumour necrosis factor (TNF) alpha, upregulated by UV exposure, may contribute to tumour escape from the immune response. In this study, we addressed whether single nucleotide polymorphisms (SNPs) in the TNFalpha promoter and lymphotoxin (LT) alpha gene are associated with susceptibility to or known prognostic indicators (e.g. initial tumour growth phase, Breslow thickness, mitotic count in vertical growth phase tumours, and tumour regression) in CMM. One hundred and forty-six British Caucasian CMM patients and 220 controls were typed for TNFalpha-376, -308 and -238 and LTalpha+252 SNPs by ARMS-PCR. Only the TNFalpha -238 GG (P = 0.05) and GA (P = 0.03) genotypes showed slight, but significant, associations with CMM, while LTalpha+252 AA was associated with a higher mitotic count in vertical growth phase tumours (P = 0.02). Both TNFalpha-238 and LTalpha+252 SNPs showed linkage disequilibrium with HLA-DQB1*0303 and *0301 alleles, variably implicated in CMM susceptibility/prognosis. In addition, TNFalpha-238, -308, LTalpha+252 haplotypes were assigned and compared. The GGA haplotype showed a modest association with CMM (P = 0.04) and with stage of disease (P = 0.03) and initial growth phase in CMM (P = 0.02), but these associations were only significant when P-values were uncorrected. Unlike basal cell carcinoma, these preliminary findings suggest that genetic variation associated with differential TNFalpha and LTalpha production is unlikely to play a major, independent role in susceptibility to, and perhaps prognosis in, CMM.