© 2018, Royal Academy of Medicine in Ireland.Background: Bladder cancer (BCa) is the seventh most common cancer among males worldwide. Some reliable markers in blood, urine, and tumor tissue, including clinicopathologic variables, molecular and inflammatory markers, gene polymorphisms, and tumor gene expression profiles are identified for predicting response to BCG immunotherapy in high-risk BCa patients. Aims: We aimed to determine if FAS and FASL polymorphisms are associated with lack of response to BCG in patients with BCa. Methods: The study included patients with primary non-muscle invasive BCa that had undergone transurethral resection (TUR). Patient demographics, BCa characteristics, use of BCG immunotherapy, lack of response to BCG (if administered), BCa recurrence, and fatty acid synthetase/fatty acid syntethase ligand (FAS/FASL) polymorphisms were investigated. Results: The study included 127 patients with primary BCa. Mean age of the 107 (84.3%) male and 20 (15.7%) female patients was 59.3 ± 13.2 years. Among the patients that received BCG immunotherapy, more FAS homozygous patients had BCa recurrence than FAS polymorphism-negative patients (P < 0.001) and more patients with homozygote FASL polymorphisms had BCa recurrence than those with heterozygous FASL polymorphisms and no polymorphism. Conclusion: Evaluation of FAS/FASL polymorphisms can predict lack of response to BCG immunotherapy and prevent the loss of valuable time before such alternative treatments as early cystectomy are initiated.