In this study, we investigated whether distinct patterns of functional genomic polymorphisms in genes involved in drug metabolic pathways (GSTT1, GSTP1, GSTM1, SULT1C2, TOP2A, SXR-1), DNA repair (XPD, XPA, ERCC1, ERCC5, XRCC1, XRCC4, XRCC5), apoptosis and inflammatory cytokines (FAS, FASL, IL-10), and multidrug resistance (MDR1-2, MDR1-6) predict clinical outcome in patients with HL. One hundred and twenty-seven adult patients (median age, 33 yrs; range, 15–80; males 53%) diagnosed with HL at a single institution between September 1995 and June 2005 have been studied. Seventeen patients (13.4%) were HIV+. Distribution according to histological subtypes was: nodular sclerosis (56.7%), mixed cellularity (20.5%), lymphocytic predominance (5.6%), and lymphoid depletion (5.6%). Epstein-Barr Virus (EBV) was present in 35.4% of the samples. First-line treatment consisted of CMOPP/ABV (39.4%) or ABVD (52.8%). Allelic discrimination of single nucleotide polymorphisms (SNPs) (ABI Prism 7500; TaqMan) of DNA obtained from formalin fixed paraffin embedded lymph nodes was performed. The characteristics considered were: age (<45 years vs. ≥45), ECOG, Hasenclever prognostic index (≤1 vs 2–4 vs ≥5), HIV status, Ann Arbor (I–II vs. III–IV), WHO histological classification, bulky disease, EBV (LMP1+ vs LMP1−), ESR (EORTC criteria), and polymorphisms of the above-mentioned genes. Clinical outcomes analyzed were probability to achieve complete remission (CR), toxicity due to the treatment, relapse rate, disease-free survival (DFS) and overall survival (OS). Out of 127 patients, 101 (79.5%) achieved CR, 7 (5.5%) partial response, 9 (7.1%) were chemoresistant, and 5 (3.9%) died during the initial treatment. After a median follow-up of 43 months (1–128), OS was 81.1% and DFS 62.6%. In the multivariate analysis, the only adverse prognostic factor for the achievement of CR was FASL -844 T>C polymorphism (RR=1.7; p=0.01) and the only adverse prognostic factor for relapse was IL-10 -1082 A>G polymorphism (RR=2.1; p=0.02). A lower probability of DFS was associated with HIV+ status (RR=11.4; p=0.03), and a lower probability of OS to higher Hasenclever prognostic index (RR=2.3; p=0.02). Moreover, a close association between Asp5Glu genotype of the phase II drug-metabolizing enzyme SULT1C2 and pulmonary toxicity was found; thus, all eight patients with pulmonary toxicity due to bleomicine had the wild type SULT1C2 genotype (p=0.006). In conclusion, germline polymorphisms in FASL, IL-10 and SULT1C2, which can easily be analyzed in paraffin embedded samples, have prognostic value in patients with HL.