Background: Differentiating passenger and driver mutations of oncogenesis is essential in understanding disease biology and developing biomarkers that use genomic mutations for diagnosis or prognostication. Accumulating research shows normal urothelium harbors many mutations commonly reported in molecular profiling of urothelial carcinoma. This is especially true of NMIBC. Here, genetic profiling of the mutational landscape of pathologic NMIBC tumors (pNMIBC) was performed and compared to matched pathologically benign urothelial tissue (pBT) to determine the frequency of passenger mutations. Methods: From a prospective observational cohort, 9 patients with high-risk NMIBC and pBT on repeat TURBT were identified. Somatic mutational profiles of the index tumor (pNMIBC) and subsequent pBT of each patient was performed via PredicineWES+ whole exome sequencing. Somatic variants were identified using the Predicine DeepSea in-house algorithm as previously described. Briefly, non-synonymous variants are captured and probabilistically annotated as germline vs. somatic in comparison with matched germline PBMC WES+ sequencing. NS somatic mutations observed in pBT were compared to those in pNMIBC to evaluate for putative passenger versus driver mutations. Results: A median of 236 mutations (IQR:100-732) were detected for pNMIBC compared to 37 (IQR: 5-80) in the pBT group (p=0.018). The number of genes with likely somatic mutations in pNMIBC only, both samples, and pBT only, were 2239, 500, and 1, respectively. The most frequently mutated genes in pNMIBC tissue samples were ARID1, TERT, CREBBP, LMTK3 and NCOR1. Notably, both pBT and pNMIBC tissue shared mutations in commonly reported bladder cancer genes such as ARID1A, ERBB2, ATM, ERCC2 and CKDN2A. Somatic mutations in FGFR3, LMTK3, NCOR1, AKAP9, COL11A2, CRYBG3, KMT2A, MCM3AP, PHF3, VPS13A and ZNF28 were present solely in pNMIBC tissue, whereas OVGP1 mutation was exclusive to pBT. Analysis of the functional impact of mutations in genes that are mutated in both benign tissue and pNMIBC offers a deeper understanding of the evolution of bladder cancer via field cancerization. Conclusions: Analysis of the mutational profile of pBT and pNMIBC revealed differential patterns of somatic mutations. Many expected gene mutations were detected in pNMIBC, but surprisingly 18% of all mutated genes were shared between tumor and pathologically benign samples. The fact that only one somatically mutated gene was exclusive to pBT signifies excellent censoring of variants by the DeepSea algorithm. In summary, these preliminary findings suggest that common gene mutations in NMIBC are frequently observed as passenger mutations. This underscores the potential significance of tissue-informed biomarkers tailored to an individual's mutational profile, which may outperform panel assays.