Recent findings suggest that genetic polymorphisms in TNF and IL10 are associated with an increased risk of non-Hodgkin lymphoma (NHL), particularly for diffuse large B-cell lymphoma (DLBCL). To further investigate the contribution of common genetic variation in key cytokine and innate immunity genes to the etiology of NHL, we genotyped participants in a case-control study of NHL conducted in Australia (545 cases, 498 controls). We investigated 36 single nucleotide polymorphisms in IL10, TNF and 21 other immune function genes. We observed an elevated risk of DLBCL with the IL10 - 3575T>A polymorphism [TA genotype: odds ratio (OR) = 1.32, 95% confidence interval (CI) = 0.86-2.02; AA, OR = 1.84, 95% CI = 1.10-3.08; trend test, P = 0.02]. Our most noteworthy TNF finding was an association between -857C>T and a decreased risk of NHL (CT or TT, OR = 0.59, 95% CI = 0.42-0.84, P = 0.003) and particularly follicular lymphoma (OR = 0.40, 95% CI = 0.23-0.68, P = 0.0009). Additionally, TNF -863C>A was associated with an elevated risk of DLBCL (CA, OR = 1.45, 95% CI = 0.95-2.21; AA, OR = 2.06, 95% CI = 0.88-4.83; trend test, P = 0.02). Our findings offer further evidence that variation in the IL10 and TNF loci influences NHL risk. Additional studies are needed to clarify the genetic and biologic basis for these relationships.