Polymorphic changes in the GSTM1, CYP2E1 and the CYP2D6 genes have been reported to be individually associated with increased susceptibility to certain cancers. In the present study, the relationship between genetic polymorphism for these genes and development of urinary bladder cancer among Egyptian patients was investigated. Our results indicate that the frequency of bladder cancer patients with the GSTM1 null genotype is significantly higher than that of the normal controls (86.3 and 47.6%, respectively) with an odds ratio (OR) of 6.97 (95% CL -1.59-30.57, Fisher's exact P = 0.008). In contrast, our investigation failed to demonstrate any difference in the distribution of CYP2E1 polymorphism between bladder cancer patients and controls as detected by PstI restriction fragment length polymorphism (RFLP) analysis. RFLP analysis of the CYP2D6 gene revealed a non-significant increase in the number of extensive metabolizers (EM) among the patients compared to the controls (68 versus 48%). However, the EM genotypes enhances the risk further for individuals harboring the GSTM1 null genotype as individuals harboring both the EM and the GSTM1 null genotypes have an odds ratio of 14.0 (95% CL = 1.3- 151.4, Fisher's exact P = 0.02) compared to individuals harboring the EM and the GSTM1 +/+ genotypes. In conclusion, our results indicate that genetic polymorphism, especially in GSTM1 and CYP2D6 could play an important role as host risk factors for development of urinary bladder cancer among Egyptians.