Therapy-related acute myeloid leukaemia/myelodysplastic syndrome (t-AML/t-MDS) results from an impaired ability to detoxify chemotherapeutic drugs or repair drug-induced genetic damage caused by genetic polymorphisms in enzymes involved in the metabolism of drugs. We analysed the prevalence of genetic polymorphisms of CYP1A12A(T6235C), CYP2E15B(C-1019T), CYP3A41B(A-290G), del{GSTT1}, del{GSTM1}, NQO12(C609T), MTHFR(C677T) and TYMS 2R/3R in 78 t-AML/t-MDS and 458 normal individuals (control group, CG) using real-time and conventional polymerase chain reaction (PCR)-based methods. The incidences of polymorphisms among t-AML/t-MDS patients and CG individuals were similar. However, a polymorphism profile consisting of CYP1A12A, del{GSTT1} and NQO12 strongly modified the risk of t-AML/t-MDS. The absence of all three polymorphisms decreased the risk of t-AML/t-MDS 18-fold (odds ratio (OR) = 0.054, 95% confidence interval (CI) = 0.005-0.63, P = 0.02), whereas the presence of only NQO1*2 or all three polymorphisms enhanced the risk of t-AML/t-MDS (OR = 2.09, 95% CI = 1.08-4.03, P = 0.03 and OR = 18.42, 95% CI = 1.59-212.76, P = 0.02 respectively). Thus, the profiles of genetic polymorphisms of drug-metabolising enzymes might explain the increased risk to t-AML/t-MDS observed in some patients treated with polychemotherapy.