e15022 Background: A marker of response to Bacillus Calmette-Guérin (BCG) intravesical therapy in high-risk non-muscle invasive bladder cancer (NMIBC) could help avoid unsuccessful BCG treatment and potentially enhance care. This study examines germline single nucleotide polymorphisms (SNPs) as markers of BCG-refractory NMIBC. Methods: Saliva or blood was prospectively collected from patients treated with BCG for NMIBC between 1991 and 2010, treated either at MSKCC or referring centers prior to MSKCC registration. BCG-refractory disease was defined as the presence of pathologically documented tumor in the bladder six months after BCG administration. SNPs were selected based on either reported associations with BCG response or putative mechanisms of BCG activity. Eighty candidate SNPs were genotyped (using the Sequenom Mass ARRAY iPLEX platform) in a discovery set (n=158) and those significantly associated were analyzed in a validation set (n=168). Univariate logistic regression was used to test the association between refractory disease, selected clinical variables, and SNPs. Because center of treatment was found to be a confounding variable (p=0.02), primary analysis was limited to cases treated at a single center (MSKCC), consisting of 276 patients (108 from discovery set and 168 from validation set). Results: Median age of diagnosis of the 276 cases was 65.7 years, 94% diagnosed with high-grade superficial bladder cancer, 35% stage Ta, 30% stage T1, and 35% stage Tis. At six month follow-up, 37 (13.4%) had BCG–refractory disease. Nine SNPs showed significant associations with outcome in the discovery cohort (two SNPs failed genotyping). In primary analysis, One SNP, rs11615, an intronic variant within the ERCC1 gene, was associated with BCG-refractory disease. Patients with CC genotype were 3.6 times more likely to be refractory to BCG compared to TT genotype (OR for each C allele was 1.8: 95% CI 1.1-3; p=0.01). No other factors were found to be predictive. Conclusions: A single nucleotide polymorphism of ERCC1 may be associated with BCG-refractory disease. Validation in independent datasets is needed.