Aim: The aim of this study was to evaluate the role of polymorphisms of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and death receptor (DR4) genes in bladder cancer susceptibility in a Turkish population. Materials and Methods: The study group included 91 bladder cancer patients, while the control group comprised 139 individuals with no evidence of malignancy. Gene polymorphisms of TRAIL C1595T (rs1131580) and DR4 C626G (rs4871857) were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. Results: The frequency of the TRAIL 1595 TT genotype was significantly lower in patients with bladder cancer compared to controls (p<0.001; odds ratios [OR]=0.143; 95% confidence interval [CI]=0.045-0.454). A significantly increased risk for developing bladder cancer was found for the group bearing a C allele for TRAIL C1595T polymorphism (p<0.001; OR=1.256; 95% CI=1.138-1.386). The observed genotype and allele frequencies of DR4 626 C/G in all groups were in agreement with the Hardy-Weinberg equilibrium (p=0.540). However, the frequency of DR4 GG genotype was found to be 2.1-fold increased in the bladder cancer patients with high-grade tumor, when compared to those having low-grade tumor (p=0.036). Additionally, combined genotype analysis showed that the frequency of TRAILCT-DR4GG was significantly higher in patients with bladder cancer in comparison with those of controls (p=0.037; OR=2.240; 95% CI=1.138-1.386). Conclusions: Our study provides new evidence that TRAIL 1595 C allele may be used as a low-penetrant risk factor for bladder cancer development in a Turkish population. Otherwise, gene-gene interaction analysis revealed that the DR4GG genotype may have a predominant effect on the increased risk of bladder cancer over the TRAIL CT genotype.