Background: Bladder cancer is one of the most common cancers worldwide. In 2022, about 81,000 people were diagnosed with this disease and 17,000 died from it (www.cancer.org). Despite significant breakthroughs in targeted medicines (i.e., Erdafitinib, FGFR2/3 kinase inhibitor) and clinical care over the past decade, non-invasive molecular testing remains an unmet clinical need for the treatment of bladder cancer patients. By contrasting the results with those from the FDA-approved tissue-based CDx assay, we assess the clinical utility of a urine NGS assay for identifying biomarkers, including mutations from FGFR genes. Methods: Paired urine and tissue samples were collected from 107 (muscle and non-muscle invasive) bladder cancer patients from the Bladder BRIDGister clinical trial in Germany. Tissue specimens were analyzed using the FDA approved Qiagen therascreen FGFR RGQ RT-PCR kit while matched urine samples were processed using the PredicineCARE urine (cell-free DNA) cfDNA NGS assay with detection sensitivity of 0.3% (0.1% for hotspot mutations). One hundred seven bladder cancer urine cfDNA NGS and tissue RT-PCR results were analyzed to determine the concordance (PPA and NPA) between these two assays. A smaller sample set was also used to compare tissue NGS to therascreen RT-PCR and tissue NGS to urine cfDNA NGS. A subset of discordant mutations were additionally validated by ddPCR. Results: For the concordance analysis between PredicineCARE Urine cfDNA NGS and therascreen tissue RT-PCR assay of 107 samples, PPA was 100% (20/20, 95% CI: 83.2-100) and NPA was 94.1% (48/51, 95% CI: 83.8-98.8). Three discrepant samples (tissue FGFR negative but urine positive for FGFR genes) were further analyzed by independent orthogonal ddPCR (Bio-Rad ddPCR Mutation Detection Assay). All tissue FGFR negative but urine positive samples were confirmed positive by ddPCR. PPA and NPA between PredicineCARE Urine cfDNA and Tissue NGS were 100% (19/19, 95% CI: 82.4-100) and 94.2% (49/52, 95% CI: 84.1-98.8) respectively. PPA and NPA between PredicineCARE Tissue NGS and Therascreen FGFR RGQ RT-PCR kit were both > 95%. Conclusions: High concordance between FGFR alterations detected with an FDA approved tissue CDx and urine cfDNA NGS assay demonstrates that the PredicineCARE urine cfDNA NGS assay may represent a novel, accurate, and non-invasive clinical application for molecular diagnostic testing to identify biomarkers in bladder cancer.