Knowledge on the impact of pharmacogenetics in predicting outcome and toxicity in diffuse large B-cell lymphoma (DLBCL) is scant. We tested 106 consecutive DLBCL treated with R-CHOP21 for 19 single nucleotide polymorphisms (SNPs) from 15 genes potentially relevant to rituximab-CHOP (R-CHOP) pharmacogenetics. Associations of SNPs with event-free survival (EFS) and toxicity were controlled for multiple testing. Genotypic variants of nicotinamide adenine dinucleotide phosphate (NAD(P)H) oxidase p22phox (CYBArs4673) and alpha1 class glutathioneS-transferase (GSTA1rs3957357) were independent predictors of EFS (CYBArs4673 TT genotype: HR 2.06,P=0.038;GSTA1rs3957357 CT/TT genotypes: HR 0.38,P=0.003), after adjusting for International Prognostic Index (IPI).CYBArs4673 andGSTA1rs3957357 also predicted outcome in DLBCL subgroups by IPI. Impact of SNPs on toxicity was evaluated in 658 R-CHOP21 courses utilizing generalized estimating equations.NCF4rs1883112 was an independent predictor against hematologic (odds ratios (OR): 0.45;P=0.018), infectious (OR: 0.46;P=0.003) and cardiac toxicity (OR: 0.37;P=0.023). Overall, host SNPs affecting doxorubicin pharmacodynamics (CYBArs4673) and alkylator detoxification (GSTA1rs3957357) may predict outcome in R-CHOP21-treated DLBCL. Also,NCF4rs1883112, a SNP of NAD(P)H oxidase p40phox, may have a function in protecting against hematologic and nonhematologic toxicity. These results highlight the need to improve characterization of the host genetic background for a better prognostication of DLBCL.