Background: The role of immunotherapy in gynecologic malignancies continues to evolve. Use of immune checkpoint blockade (ICB) agents have consistently demonstrated less than a 15% response rate in ovarian, cervical, and subsets of endometrial cancer. Given the limited number of responders, a novel approach to treatment monitoring is needed to better sequence therapies. Circulating tumor DNA (ctDNA) surveillance in patients treated with ICB is one such approach that has been shown to predict clinical benefit. We sought to evaluate this approach in patients with recurrent gynecologic malignancies managed with ICB therapy. Methods: In this retrospective analysis of real-world data, plasma samples (n = 208) from 28 patients with recurrent/metastatic ovarian (n = 8), endometrial (n = 14), and cervical (n = 6) cancers were identified as having received ICB therapy. A personalized and tumor-informed multiplex PCR assay (Signatera™ bespoke mPCR NGS assay) was used for the detection of ctDNA in plasma samples. Serial time points were collected to monitor ctDNA levels in response to immunotherapy. Results: Response assessment results and longitudinal plasma samples were available for 19 patients. Pre-ICB plasma samples were available for 11 patients. Of these ctDNA was detected in 73% (8/11) of patients. All patients with progressive disease (10/10) had rising ctDNA levels that preceded radiological findings by a median of 2.8 months. One patient with rising ctDNA concentration presented with stable disease by imaging at the last follow-up. The remaining 8 patients demonstrated response to therapy that coincided with a declining or negative ctDNA level; 5 with partial response had a decline in ctDNA level prior to imaging (n = 3) or lack of ctDNA detection (n = 2), and 3 with complete response remained ctDNA negative, prior to imaging. Patients that exhibited a rise in ctDNA concentration (n = 11) (consecutive time points) while undergoing ICB therapy were associated with resistance to treatment (HR = 4.58 95%CI: 1.048-20.03, p = 0.04). TMB and MSI status (binary) were not predictive of response in univariate (p = 0.8, p = 0.9) analyses. Conclusions: ctDNA monitoring during the course of immunotherapy for relapsed gynecologic malignancies allows for accurate determination of therapeutic response and early prediction of disease progression. This enables timely assessment with imaging, and change in treatment plan. Our data suggest that patients with gynecologic malignancies may benefit from personalized, tumor-informed ctDNA testing to guide treatment decisions. Prospective studies are needed to establish the clinical utility of ctDNA monitoring in patients with gynecologic malignancies undergoing systemic therapies.