In this study we tested whether distinct patterns of functional genomic polymorphisms in genes involved in drug metabolic pathways (GSTT1, SULT1C2, CD-EX, TOP2A, SXR-1, SXR-2), DNA repair (XPD, XPA, XPG, ERCC1), angiogenesis (VEGF-1, VEGF-2), and multidrug resistance (MDR1-1, MDR1-2) predict clinical outcome in patients with AML. Two hundred adult patients ≤60 year-old with primary AML (M3 excluded), enrolled in the AML-99 protocol of the CETLAM group between November-98 and July-03, have been studied. Induction therapy consisted of idarubicin, intermediate dose ara-C (IDAC) and VP16. Intensification included mitoxantrone and IDAC. Patients were following treated with high-dose ara-C or transplantation depending on the risk category. According to the MRC cytogenetic classification, 32 patients had a favourable karyotype, 23 had abnormalities indicating poor prognosis, and 110 patients were included in the intermediate prognosis (IP) group. We focused on IP group patients with the aim of improving its prognostic stratification. The characteristics considered were: age (<50 years vs ≥50), WBC (≤20x109/l vs >20x109/l), FAB classification, MLL rearrangement, internal tandem duplication of FLT3 (ITD-FLT3), induction courses to achieve complete remission (CR) (1 vs 2), and germline polymorphisms of the above-mentioned genes. Prognostic variables in the univariate analysis (Kaplan-Meier method) with a p value ≤0.2 (log-rank test) were included for the multivariate analysis (proportional hazard method). Of the 110 patients included in the IP group, 86 (78%) achieved a CR, 11 (10%) were chemoresistant and 13 (12%) died during induction. After a median follow-up of alive patients of 24 months (range 5–64), overall survival was of 31% at 5 years. In the multivariate analysis, adverse prognostic variables for survival were polymorphism of XPA (RR=3.4; p=0.02) and of MDR1-1 (RR=2.1; p=0.02), and WBC >20x109/l (RR=2.1; p=0.02). Increased risk of relapse was associated with polymorphism of SULT1C2 (RR 4.1; p=0.004), ITD-FLT3 (RR 3.3; p=0.003), VEGF2 (RR 2.8; p=0.04) and MDR1-1 (RR 2.4; p=0.02). Finally, in the multivariate analysis for refractoriness to chemotherapy, XPA polymorphism was the only independent factor increasing the risk (RR=14; p=0.02). In conclusion, germline polymorphisms, which can easily be analyzed from DNA of peripheral blood, have independent prognostic value in intermediate risk AML.