Background: Adjuvant Osimertinib (Osi) was recently approved for resected EGFR-mutant non-small cell lung cancer (NSCLC) based on disease free survival (DFS) benefits from the ADAURA trial. Prior studies of adjuvant EGFR inhibitors yielding DFS benefits have lacked an overall survival (OS) benefit, leading to debate over early clinical implementation given the associated drug costs. This study aims to evaluate the cost-effectiveness (CE) of Osi in this setting. Methods: We constructed Markov models using post-resection health state transitions with digitized DFS data from the ADAURA trial to compare cost and quality-adjusted life years (QALYs) of the use of 3 years of adjuvant Osi versus placebo in the ADAURA patient population of stage IB to IIIA NSCLC patients over a 10-year time horizon. All patients entering the progressive disease (PD) state were assigned for re-treatment with Osi. Cost and utility values were derived from Medicare reimbursement data and literature (Table). A CE threshold of 3 times the GDP per capita was used. Deterministic sensitivity analyses were performed to assess the impact of a range of OS benefit, as the impact of adjuvant Osi on OS has not yet been reported. Results: The incremental cost-effectiveness ratio (ICER) for adjuvant Osi was $317,119.90 per QALY gained. Initial costs of Osi are higher in the first 3 years, but become lower than the placebo group in year 4 onward, with similar costs after year 7. Costs due to PD are higher in the placebo group through the first 6.5 years. Average pre-PD, post-PD, and total costs were $2,388, $379,047, and $502,937, respectively in the placebo group, compared to $505,775, $255,638, and $800,697, respectively in the Osi group. QALYs were higher in the Osi arm throughout. Sensitivity analysis using incremental OS gains reaches the CE threshold of $195,000 between 25-30% OS benefit of Osi over placebo. A 50% discount to the Osi annual cost yielded an ICER of $115,419. Conclusions: 3 years of adjuvant Osi is more cost-effective than placebo if one is willing to pay $317,119 more per QALY gained, with most costs accruing in the first 3 years as drug cost. This strategy became cost-effective with an OS benefit between 25-30% over placebo. Discount to Osi annual costs improves the ICER significantly. True cost-effectiveness of adjuvant Osi will require further study due to immaturity of ADAURA OS data and model limitations.