Cytokines mediate many immune and inflammatory responses contributing to tumorigenesis. The present study evaluated polymorphisms of IL4, IL6, and TNF (previously TNFA) genes influencing risk in development of transitional cell carcinoma of bladder and recurrence after bacillus Calmette-Guérin (BCG) immunotherapy. The study included 136 unrelated histopathologically confirmed cases and 200 population-based controls. Genomic DNA was extracted from peripheral leukocytes and genotyped for polymorphism in IL4 intron 3, with point mutations identified by amplification refractory mutation system polymerase chain reaction (ARMS-PCR) in IL6-174 G/C and by PCR-restriction fragment length polymorphism analysis in TNF-308 G/A. The IL6 variant C/C exhibited significant association with bladder cancer risk (odds ratio OR = 2.811, P = 0.004), but IL4 and TNF genetic variants did not. Significant association was observed for IL4 (B1/B2+B2/B2) with high-grade or late-stage tumor for TaG3+T1 and T2+ (OR = 5.950, and 6.342 respectively) and with smoking (P = 0.004, OR = 4.202). Low recurrence risk was observed in BCG-treated patients carrying C/C genotype of IL6 (hazard ratio = 0.298, P = 0.03), and also higher recurrence-free survival (log rank P = 0.021). TNF and IL4 demonstrated no association of bladder cancer risk and BCG therapy. The low-producing variant C/C of IL6 may be a risk factor for bladder cancer, whereas high-producing genotypes of IL4 (B1/B2+B2/B2) may predispose to higher risk in patients with high-grade or late-stage tumor and smoking habits. The low-producing C/C IL6 genotype, which favors Th1 response, may be a beneficial prognostic indicator for treatment and survival of BCG-treated patients. © 2008 Elsevier Inc. All rights reserved.