Aims: We investigate the value of postoperative minimal residual disease (MRD) detection using circulating tumor DNA (ctDNA) in guiding adjuvant therapy for patients with potentially high recurrence risk in non-small cell lung cancer (NSCLC) due to the presence of MRD. Patients and Methods: A randomized controlled trial will enroll stage IA-IIA NSCLC patients with Epidermal Growth Factor Receptor (EGFR) mutation and negative resection margins to evaluate the clinical value of MRD in guiding adjuvant osimertinib. That is, if the patient's peripheral blood does not show ctDNA (negative) after next generation sequencing (NGS) testing, postoperative observation and followup are sufficient. Conversely, if ctDNA is positive, the patient will be randomly assigned to two groups and receive adjuvant treatment with osimertinib or observation and follow-up. In total 1068 postoperative patients should be recruited, finally, 32 MRD positive patients were divided into a treatment group or an observation group. Primary endpoint: progression-free survival (PFS). Secondary endpoints: 2- and 5-year PFS rates, regimen safety, and tolerability. Exploratory indicator in the MRD-positive group: ctDNA clearance rate at 12 and 24 months. Results and conclusions: This study provides crucial insights into therapy guidance for EGFR-mutated NSCLC patients with MRD, potentially enhancing patient outcomes.