Background: Altered DNA repair capacity due to polymorphisms in DNA repair genes may modify response to Bacillus Calmette-Guerin (BCG) immunotherapy for high risk uperficial bladder cancer (SBC).We evaluated the prospective outcome of exicision repair cross complementing group 2 (ERCC2) and apurinic/ apyriminidic endonuclease (APEX1) gene in tumor recurrence after BCG immunotherapy in SBC patients. Materials and methods: The study included 135 SBC patients, of which BCG immunotherapy was received by 74 patients. Genotyping was performed for ERCC2 Asp312Asn (G>A), Lys751Gln (A>C), and APEX1 Asp148Glu (T>G) polymorphisms by restriction fragment length polymorphism PCR and amplification refractory mutation system (ARMS) methods. Results: Multiple Cox regression analysis demonstrated association of variant genotype of ERCC2 312AA polymorphism with high risk of recurrence in BCG treated patients (HR = 3.07, P = 0.016, Pc = 0.048). Patients with the ERCC2 312AA polymorphic genotypes showed shorter recurrence free survival (log-rank, P = 0.005; AA/GA ? AA = 14/44) who received BCG treatment. Overall, risk of recurrence in bladder cancer was observed with smokers and size of tumors (1-3 cm) (HR = 1.86, P = 0.023 and HR = 3.19, P = 0.031, respectively). Smokers were identified to be at elevated risk in BCG treated patients (HR = 2.84, P = 0.005). No association was observed with the (ERCC2 Lys751Gln and APEX1 Asp148Glu) polymorphisms and risk of recurrence. Conclusion: Our data suggested variant (AA) of ERCC2 312 AA genotype to be associated with high risk of tumor recurrence and reduced recurrence free survival in superficial bladder cancer patients. ©2009 Humana Press Inc.