Interleukin-12 (IL-12) as an antitumor and interleukin-6 (IL-6) as an inflammatory cytokine, areimmunomodulatory products that play important roles in responses in cancers and inflammation. We testedthe association between two polymorphisms of IL-12(1188A>C; rs3212227) and IL-6 (-174 C>G) and the riskof bladder cancer in 261 patients and 251 healthy individuals. We also investigated the possible association ofthese SNPs in patients with high-risk jobs and smoking habits with the incidence of bladder cancer. The genotypedistributions of IL-6 (-174 C/G) genotype were similar between the cases and the control groups; however, amongpatients with smoking habits, the association between IL-6 gene polymorphism and incidence of bladder cancerwas significant. After a control adjustment for age and sex, the following results were recorded: CC genotype(OR= 2.11, 95%CI=1.56-2.87, p=0.007), GC genotype (OR=2.18, 95%CI=1.16-4.12, p=0.014) and GC+ CC(OR=2.6, 95%CI=1.43-4.47, p=0.011). A significant risk of bladder cancer was observed for the heterozygousgenotype (AC) of IL-12 (OR=1.47, 95%CI=1.01-2.14, p=0.045) in all cases, and among smokers (AC) (OR=3.13,95%CI=1.82-5.37, p=0.00014), combined AC+CC (OR=3.05, 95%CI=1.8-5.18, p=0.000015). Moreover amonghigh risk job patients, there was more than a 3-fold increased risk of cancer in the carriers of IL-12 betaheterozygous (OR=3.7, 95%CI=2.04-6.57, p=0.000056) and combined AC+CC(OR=3.29, 95%CI=1.58-5.86,p=0.00002) genotypes as compared with the AA genotype with low-risk jobs. As a conclusion, this study suggeststhat IL-12(3’UTR A>C) and IL-6 (-174 C>G) genotypes are significantly associated with an increased risk ofbladder cancer in the Iranian population with smoking habits and/or performing high-risk jobs.