Hodgkin lymphoma is a highly curable malignancy, but treatment outcome might be influenced by inherited gene polymorphisms determining anticancer agent metabolism. We prospectively collected peripheral blood lymphocytes from 313 patients with Hodgkin lymphomas to analyze GSTP1, GSTM1, GSTT1, UGT1A1, and CYP3A4 enzyme gene polymorphisms. All patients were treated with chemotherapy, associated with radiotherapy when they had localized disease. There was no difference for GSTP1, GSTM1, and GSTT1 as well as for UGT1A1 and CYP3A4 polymorphism distributions between Hodgkin lymphoma patients and healthy controls. Patients carrying 1 or 2 UGT1A1*28 allele had a significantly (P < .05) better freedom from progression and time to treatment failure than those homozygous for the UGT1A1 TA6/TA6 allele. Multivariate prognostic analyses showed that the UGT1A1 polymorphism was as an independent prognostic parameter for all the studied endpoints, the wild-type homozygous UGT1A1 TA6/TA6 genotype being associated with a significantly worse prognosis than genotypes with at least one UGT1A1*28 allele (overall survival; relative risk [RR] = 2.54, 95% confidence interval [CI], 1.05-6.14; P = .04; freedom from progression, RR = 2.70, 95% CI, 1.37-5.31; P = .004; time to treatment failure, RR = 2.37, 95% CI, 1.28-4.40, P = .006). UGT1A1 polymorphism on TA repeats, which are thought to determine several anticancer drugs metabolism, influence Hodgkin lymphoma patient outcome.