Despite surgery with curative intent, approximately 30% of patients with primary bladder cancer (BCa) will suffer from a recurrence, with over half of those occurring within 12 months post surgery. More precise clinical diagnostic tools are warranted in the context of BCa to predict response to therapy and monitor minimum residual disease to minimize metastatic progression. A peripheral blood sample utilized as a form of liquid biopsy can be used to predict metastasis in primary BCa patients prior to cystectomy. The liquid biopsy can indicate which patients have a more advanced form of cancer and to help steer treatment options, such as whether neoadjuvant chemotherapy would be beneficial or if surgery is necessary at all, significantly optimizing treatment pathways for the individual patient. Circulating tumor cells (CTCs) and circulating cell-free DNA (cfDNA) detected in the peripheral blood have been demonstrated as useful tumor biomarkers and may be associated with poor prognosis and early relapse. The third-generation comprehensive liquid biopsy used here is the high-definition single-cell assay (HDSCA3.0) workflow for the analysis of the liquid biopsy collected from primary BCa patients prior to cystectomy to provide initial evidence for clinical utility. Circulating cfDNA and CTCs found in the liquid biopsy of BCa patients may provide critical evidence to support clinical decision making to improve both patient care and outcomes. Using clinical data elements, we will determine the significance of HDSCA data in predicting relapse. This is a unique opportunity to provide pathology quality data from the blood to assist in BCa patient care.