OBJECTIVES: To evaluate the role of circulating tumor DNA (ctDNA) as a prognostic and predictive biomarker in the perioperative management of muscle-invasive bladder cancer (MIBC). METHODS: We conducted a systematic literature review using PubMed, MEDLINE, and Embase, following PRISMA guidelines. Studies from January 2013 to March 2024 were included if they examined ctDNA in MIBC patients undergoing radical cystectomy (RC) and perioperative chemotherapy or immunotherapy. RESULTS: Eight studies were included. ctDNA detected before RC was associated with poor recurrence-free survival and higher risk of nodal and locally advanced disease. Postoperative ctDNA levels correlated with shorter disease-free survival and higher recurrence rates. ctDNA clearance during neoadjuvant chemotherapy was predictive of treatment response. ctDNA status post-neoadjuvant immunotherapy correlated with pathological outcomes and recurrence rates. CONCLUSIONS: ctDNA is a promising biomarker for predicting oncological outcomes in MIBC, with potential to guide perioperative treatment decisions. Further randomized controlled trials are needed to validate these findings.