The cytokines tumour necrosis factor-alpha (TNFalpha) and lymphotoxin-alpha (LTalpha) are known to play key roles in B-cell growth, differentiation and maturation. Genetic polymorphism within regulatory regions of these cytokine genes can alter expression levels and may be important in development of lymphoid malignancy. This study investigates a number of single nucleotide polymorphisms (SNPs) and microsatellite variants present within these genes in a large cohort of non-Hodgkin lymphoma (NHL) cases including 211 cases of follicular lymphoma (FL) and 281 cases of diffuse large B-cell lymphoma (DLBCL), and 478 unaffected controls. The study investigated whether particular alleles at these loci, or their combination across the TNF region in the form of haplotypes, may act as markers for predisposition and development of NHL. The study provided evidence for an influence of the TNF region in the susceptibility to NHL, whereby the loci -863, -857, TNFe and TNFd categorised five haplotype groups over which risk of both FL and DLBCL varied significantly. Prediction of disease risk was improved by the addition of loci to the haplotype, demonstrating the importance of considering the haplotype-specific context of the loci in genetic risk assessment.