Abstract Secreted Protein Acidic and Rich in Cysteine (SPARC), also termed osteonectin and BM-40, exhibits highly regulated expression during normal development, in tissues undergoing remodeling and repair as well as in cancer. The role of SPARC in bladder cancer is still elusive. Therefore, we sought to investigate the differential roles of SPARC in bladder carcinogenesis, progression and metastasis. We developed a chemical carcinogen N-nitrosobutyl(4-hydroxybutyl) amine (BBN) fed to mice with targeted deletion of SPARC (SP−/−) and their wild type counterparts (SP+/+) in drinking water to induce bladder cancer. We found that SP−/− mice exhibited earlier onset of urothelial pathology (inflammation/atypia and dysplasia, P<0.01) that significantly rapidly progressed to carcinoma in situ (CIS, P<0.02) and muscle invasive disease (P<0.03) as compared to their SP+/+ counterparts. SP−/− mice also exhibited significantly higher incidence and frequency of multifocality (kidney involvement, P<0.02) as well as metastases to para-aortic lymph nodes (P<0.04) and lungs (P<0.03) than SP+/+ counterparts. Furthermore, SP−/− mice had significantly lower median survival than SP+/+ counterparts (27weeks versus 40weeks for SP−/− and SP+/+, respectively; P<0.0002). Comparative analysis of bladder tissue lysates harvested from SP−/− and SP+/+ mice with matched pathology and BBN-exposure revealed that the accelerated onset of bladder lesions in SP−/− compared to SP+/+ was due to the effect of SPARC inhibiting cell cycle progression. These effects correlated with increased accumulation of reactive oxygen species concomitant with DNA damage as determined by 8-OH-odeoxyguanosine, lipid peroxidation and increase in markers of protein oxidation, sulfiredoxin and nicotinamide-N-methyl transferase (NNMT). The significant increase in inflammation in SP−/− was associated with significant higher activation of transcription factors AP1 and NFκß compared to SP+/+. These findings indicate SPARC exerts distinct differential roles in modulating tumor-host interactions during the initiation, progression and lung metastasis of bladder cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 913. doi:10.1158/1538-7445.AM2011-913