We analyzed the allelic distribution of 12 candidate polymorphisms in a large retrospective study of 486 patients with diffuse large B-cell lymphoma (DLBCL) treated at Oslo University Hospital with 1056 blood donors serving as controls. Variants in TNFα (rs1800629) (GG vs. AG/AA, p < 0.001) and LTA (rs909253) (AA vs. AG/GG, p = 0.02) and deletions in GSTM1 and GSTT1 (undeleted vs. deleted, p = 0.01 and p = 0.01, respectively) were associated with increased susceptibility of developing DLBCL. IL-10 (rs1800896) variants (GG vs. AG/AA, p = 0.03) were associated with decreased susceptibility. In line with several previous reports, patients carrying the TNFα (rs1800629) A allele treated in the pre-rituximab era had inferior outcome compared to patients carrying the homozygous GG genotype (p = 0.004, n = 33). However, patients receiving at least one dose of rituximab had equal outcome regardless of their TNFα genotype (HR = 0.94, p = 0.79, n = 307). Deletion in GSTM1 was associated with inferior outcome for patients with low International Prognostic Index (IPI) score (p = 0.04). Our findings support the suggestions that polymorphisms in genes encoding immunoregulatory proteins and enzymes that metabolize carcinogens and chemotherapeutic drugs influence DLBCL susceptibility and possibly treatment outcome. The influence of polymorphisms in immunoregulatory genes on outcome in DLBCL should be reevaluated in the rituximab era.