Objective. Urinary bladder neoplasms differ considerably in biological potential, and tumor morphology alone cannot predict their clinical behaviors. Polymorphisms in xenobiotic metabolic genes reportedly modulate susceptibility to bladder neoplasms and may affect the clinical course and outcomes of the disease. This study was conducted to determine the effect of polymorphisms in the xenobiotic metabolic genes on the disease course and clinical outcomes of urinary bladder neoplasms. Material and methods. Patients with urinary bladder neoplasms who had been followed up for a 5-year period were genotyped for NQO1 (R139W, P187S), NAT (rapid/slow), GSTP1 (I105V), GSTT1 and GSTM1 (non-null/null) and MTHFR (A222V, E429A) polymorphisms. Results. Variant allele carriers of the NQO1 (P187S) polymorphism showed a higher risk for high-stage disease than non-carriers at diagnosis [relative risk (RR)=1.4; 95% CI 1.0-1.8). A higher risk for highly malignant disease (T2+) was also observed in variant allele carriers than non-carriers of the GSTP1 (I105V) polymorphism (RR=1.6; 95% CI 1.1-2.5). NQO1 (R139W) variant allele carrier patients with intermediate malignant disease (TaG3+T1) had shorter disease-free survival than non-carriers (p=0.05). In contrast, carriers of the variant allele for the MTHFR (A222V) polymorphism had significantly longer disease-free survival than non-carriers (p=0.02). Conclusions. Our data are consistent with the notion that NQO1 polymorphisms influence the course and clinical outcomes of urinary bladder neoplasms. However, our results need to be confirmed in a large study as most of the associations detected were only of marginal statistical significance, and would be lost on correction for multiple comparisons.