Background <p>Early detection of melanoma recurrence and progression remains a clinical challenge, which relies on physical examination and imaging. Circulating tumor DNA offers a noninvasive, dynamic biomarker that may identify molecular recurrence before clinical progression. We aimed to evaluate the prognostic and predictive value of longitudinal, tumor-informed ctDNA testing across multiple melanoma care settings.</p> Methods <p>We retrospectively analyzed 56 consecutive melanoma patients who underwent serial ctDNA testing using a tumor-informed assay (Signatera™) at a single institution. Fifty-six patients with evaluable ctDNA results were stratified into three cohorts based on the treatment context at the time of ctDNA testing: (A) no active treatment (<i>n</i> = 20), (B) adjuvant therapy (<i>n</i> = 14), and (C) active treatment for known disease (<i>n</i> = 22). We evaluated disease-free survival (DFS), overall survival (OS), and longitudinal ctDNA dynamics in relation to clinical outcomes.</p> Results <p>Median clinical follow-up was 48.0 (IQR 24.7–94.1) months. In Cohorts A and B (HR 12.3, 95% CI 1.1–1138.6), detectable ctDNA at any timepoint was significantly associated with inferior DFS. Conversely, 90% of patients in Cohorts A and B combined with undetectable ctDNA remained recurrence-free. In Cohort C, rising or persistently positive ctDNA was seen in 81.8% of patients who progressed. Longitudinal ctDNA trends were more informative than isolated timepoints, with increases preceding radiologic progression by a median of 11.4 (IQR 5.0–13.1) months.</p> Conclusions and relevance <p>Tumor-informed ctDNA testing offers clinically meaningful insight across melanoma care settings. Rising or positive ctDNA frequently anticipates disease progression, supporting its use for MRD surveillance and treatment response monitoring in dermatology and oncology practice.</p>