Using 1996-2000 data among Connecticut women, the authors evaluated whether genetic variation in 4 metabolic genes modifies organic solvent associations with non-Hodgkin lymphoma and 5 major histologic subtypes. P(interaction) values were determined from cross-product terms between dichotomous (ever/never) solvent variables and genotypes at examined loci in unconditional logistic regression models. The false discovery rate method was used to account for multiple comparisons. Overall associations between the chlorinated solvents dichloromethane (odds ratio (OR) = 1.69, 95% confidence interval (CI): 1.06, 2.69), carbon tetrachloride (OR = 2.33, 95% CI: 1.23, 4.40), and methyl chloride (OR = 1.44, 95% CI: 0.94, 2.20) and total non-Hodgkin lymphoma were increased among women TT for rs2070673 in the cytochrome P4502E1 gene, CYP2E1 (dichloromethane: OR = 4.42, 95% CI: 2.03, 9.62; P(interaction) < 0.01; carbon tetrachloride: OR = 5.08, 95% CI: 1.82, 14.15; P(interaction) = 0.04; and methyl chloride: OR = 2.37, 95% CI: 1.24, 4.51; P(interaction) = 0.03). In contrast, no effects of these solvents were observed among TA/AA women. Similar patterns were observed for diffuse large B-cell lymphoma and follicular lymphoma, as well as marginal zone lymphoma for dichloromethane. The weak, nonsignificant overall association between benzene and diffuse large B-cell lymphoma (OR = 1.29, 95% CI: 0.84, 1.98) was increased among women AA for rs2234922 in the microsomal epoxide hydrolase gene, EPHX1 (OR = 1.77, 95% CI: 1.06, 2.97; P(interaction) = 0.06). In contrast, no effect was observed among AG/GG women. Additional studies with larger sample size are needed to replicate these findings.