Background: The clinical utility of circulating tumor DNA (ctDNA) in the early detection of tumor mutations for targeted therapy and the monitoring of tumor recurrence has been reported. However, the analytical validation of ctDNA assays is required for clinical application. Methods: This study evaluated the analytical performance of the Oncomine Lung cfDNA Assay compared with the cobas®EGFRMutation Test v2. The analytical specificity and sensitivity were estimated using commercially pre-certified reference materials. The comparative evaluation of the two assays was carried out using reference materials and plasma derived from patients diagnosed with lung cancer. Results: Using 20 ng of input cell-free DNA (cfDNA), the analytical sensitivities forEGFRmutations with variant allele frequencies (VAFs) of 1% and 0.1% were 100% and 100%, respectively. With VAFs of 1.2% and 0.1% using 20 ng of input cfDNA, seven out of nine different mutations in six driver genes were identified in the Oncomine Lung cfDNA Assay. The two assays showed 100% concordance in 16 plasma samples clinically. Furthermore, variousPIK3CAand/orTP53mutations were identified only in the Oncomine Lung cfDNA Assay. Conclusions: The Oncomine Lung cfDNA Assay can be used to identify plasmaEGFRmutations in patients with lung cancer, although further large-scale studies are required to evaluate the analytical validity for other types of aberrations and genes using clinical samples.