Background: Emerging data suggest a role for targeted therapy in patients (pts) with mUC whose tumors contain actionable genomic alterations (GA). Liquid biopsy of ctDNA from blood provides an attractive alternative for CGP in pts in whom tissue-based testing is not feasible. Methods: Hybrid capture-based genomic profiling was performed using FoundationACT assay in a CLIA-certified, CAP-accredited, NY State-approved laboratory. Cell free DNA was extracted from plasma using 20 ml whole blood and underwent CGP of 62 genes. Sequencing was performed to a median unique coverage of 6756× using the Illumina HiSeq 2500/4000 platform. Barcode-based error correction enabled analysis of GA at low allele frequency (AF), including base substitutions and short in/dels (AF≥0.1% for both), rearrangements, and copy number amplification. For several pts, non-temporally matched tissue-based CGP data was available. Comparisons to other CGP datasets of UC ctDNA and tissue were performed. Results: 66 pts with median age 68 (range 29-86) underwent ctDNA assessment as clinical test. There was evidence for ctDNA in 56 pts (85%), and ≥1 GA was noted in 48 pts (73%). The estimated median ctDNA fraction in plasma was 1.9%. In cases with detectable ctDNA, the most frequently altered genes were TP53 (68%), TERT-promoter (38%), PIK3CA (13%), FGFR3 (13%), KRAS (11%), NF1 (6%), ERBB2 (6%). Observed GA frequencies were comparable to prior studies of ctDNA and tissue. Both tissue and ctDNA-based CGP data with clinical correlation was available for several pts. A pt with FGFR3 GA in baseline tumor tissue had disappearance of FGFR3 GA and detection of new TP53 GA in ctDNA after targeted treatment with FGFR3 inhibitor. In a pt with ERBB2 and TP53 GAs in baseline tumor tissue, ctDNA at time of resistance to cisplatin-based therapy showed persistence of ERBB2 and TP53 GAs and new NF1 GA. Conclusions: Most pts with mUC had detectable ctDNA, and frequencies were comparable to prior data sets Detection of potentially targetable GA support further clinical utility assessment. Concordance between tissue and ctDNA in temporally matched samples with clinical annotation warrants further investigation.