In the present study, we investigate whether genetic polymorphism in enzymes involved in the metabolism of organic solvents influences susceptibility to chronic solvent encephalopathy (CSE), which is one of the major effects of long-term exposure to organic solvents. Polymorphisms in the genes encoding CYP1A1, CYP2E1, EPHX1, GSTM1, GSTT1 and GSTP1 enzymes were determined in a group of male CSE patients (N=97) and controls (N=214). The selection of the patients was based on a standard diagnostic protocol, including interviews, neuropsychological tests and questionnaires directed to somatic, cognitive and mood symptoms and exposure, in combination with well-defined decision rules. As controls, healthy workers of similar socio-economic background, without memory problems and with no known exposure to organic solvents, were included in the study. Comparing patients and controls, higher frequencies of the variant *5B allele of the CYP2E1 gene (OR: 5.8; 95% CI: 1.8-18.8) and of the variant GSTP1*C allele (OR: 0.40; 95% CI: 0.17-0.94) were found. Homozygous carriers of the exon 4 EPHX1 Arg139 variant allele had a lower risk (OR: 0.25; 95% CI: 0.06-1.13). The present study indicates that genetic polymorphism of CYP2E1, EPHX1 and GSTP1 modify the risk of developing CSE.