Background: Serum-based tumor markers (STM) (AFP, LDH, and b-hCG) used as standard of care in patients with testicular cancer lack sufficient sensitivity and specificity for molecular residual disease (MRD) detection. Although circulating tumor (ct) DNA holds promise as a prognostic biomarker in a variety of malignancies, its clinical utility in testicular cancer has not been well characterized. This study evaluates the utility of longitudinal ctDNA monitoring for MRD detection in patients with testicular cancer. Methods: Retrospective ctDNA analysis was performed using a personalized, tumor-informed ctDNA assay (SignateraTM bespoke mPCR-NGS assay). ctDNA was evaluated during the MRD [1-12 weeks post-orchiectomy] and surveillance [>12 weeks post-orchiectomy, post-adjuvant chemotherapy (ACT), or after retroperitoneal lymph node dissection (RPLND)] windows. Correlation between ctDNA status and patient outcomes (event-free survival (EFS)) was assessed. EFS is described as the interval from radical orchiectomy to the date of radiological recurrence or any evidence of residual/persistent disease after the completion of ACT or RPLND. A clinical nomogram was developed to predict clinical outcomes based on age, stage, histology, presence of STMs, and ctDNA during the surveillance window. This point system calculates the 1 2-year EFS probability with patients receiving points between 0-200. Results: A total of 145 plasma samples were collected from 35 patients with stages I-III testicular cancer (%stage I/II/III: 66/23/11; %seminoma/non-seminoma: 49/51). Post-operatively, 43% (15/35) of these were on surveillance, 23% (8/35) received ACT, 8.6% (3/35) underwent RPLND, and 26% (9/35) underwent RPLND and received ACT. The median age of the cohort was 34 years (IQR: 29-42) with a median follow-up of 10 months (IQR: 6.5-18.7).Pre-orchiectomy (N=15), ctDNA was detected in 91.6% (11/12) of stage I and 100% of stage II/III (3/3)) patients.During the MRD (N=22) and surveillance (N=27) windows, patients who tested ctDNA positive showed a significantly inferior EFS compared to those who tested negative (MRD: HR 7.2, 95% CI: 1.4-36.7, p=0.017 and Surveillance: HR 11.8, 95% CI: 2.3-59.1, p=0.003). Multivariate regression analysis during surveillance revealed any-time ctDNA-positivity as the only factor significantly associated with poor EFS (p=0.015) when compared to other clinicopathological features such as age, stage, histology, and elevated STMs. Conclusions: This is the first study that utilizes longitudinal tumor-informed ctDNA testing to assess patient outcomes and disease status. Our results suggest that tumor-informed ctDNA analysis may hold promise as a biomarker for EFS in patients with testicular cancer. As such, we developed the first-ever clinical nomogram that includes ctDNA status and other clinicopathological factors to stratify patient outcomes.