Abstract: Objective To explore the application of droplet digital PCR (ddPCR) in detecting circulating tumor DNA (ctDMA) in epidermal grouth factor (EGFR) mutations in advanced lung adenocarcinoma patients. Methods A total of 38 patients with advanced lung adenocarcinoma who were admitted to the First People's Hospital of Lianyungang from October 2023 to October 2024 were selected. All patients were diagnosed with EGFR mutations through tissue paraffin-embedded gene testing and received EGFR-tynsine kinase in hibitor (EGFR-TKI) treatment. Peripheral blood samples were collected before treatment (baseline) and 1 month after treatment to detect ctDNA EGFR mutations. The clinical value of ddPCR in detecting ctDNA EGFR mutations was analyzed. Results In the baseline plasma of 38 EGFR mutation-positive advanced lung adenocarcinoma patients, ctDNA EGFR mutations were detected in 26 cases, with a positive detection rate of 68.4%. One month after treatment, 12 patients had persistently negative ctDNA EGFR mutations, and 54% (14/26) of patients had ctDNA cleared after treatment. The EGFR mutation gene abundance in patients with persistent ctDNA after treatment was significantly lower than that before treatment (P=0.028). Multivariate Cox regression analysis showed that baseline brain metastasis (HR=3.898, 95%CI: 1.138-13.359, P=0.030) and ctDNA EGFR positive mutation 1 month after treatment (HR=8.861, 95%CI:2.324-33.840, P=0.001) were inderpendent factors influencing progression free survival (PFS) in patients nith advanced lung adenocarcinome. Kaplan-Meier survival curve analysis showed that patients with ctDNA EGFR positive mutation 1 month after treatment had significantly shorter PFS than those with negative mutations (median PFS: 8.3 months vs. not reached, P<0.001). Furthermore, patients whose ctDNA EGFR mutation became negative after treatment were included in the "clearance" group, while those with persistent ctDNA EGFR mutations after treatment or those with negative ctDNA EGFR mutations before and after treatment were included in the "stable" group. The clearance group had significantly longer PFS than the stable group (median PFS: not reached vs. 13.0 months, P=0.016). Conclusions The early changes in ctDNA EGFR mutations detected by ddPCR have potential clinical application value in predicting the prognosis of advanced lung adenocarcirnma patients.