BACKGROUND: There is an urgent need to develop a convenient and less invasive technique to monitor the efficacy of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) in patients with EGFR-mutated non-small-cell lung cancer (NSCLC). We proposed folate receptor-based assay to count circulating tumor cells (CTCs) to predict and dynamically monitor the therapeutic response to first-line EGFR-TKIs in patients with EGFR-mutated NSCLC. PATIENTS AND METHODS: Eligible patients were enrolled, and 3 mL of blood was obtained before initial treatment, 1 month after treatment, and every 2 months thereafter. CTCs were isolated on the basis of negative enrichment by immunomagnetic beads and detected by a ligand-targeted PCR method. RESULTS: A total of 232 patients with EGFR-mutated NSCLC and treated with first-line EGFR-TKIs were included. Patients with low baseline CTC count had a markedly longer progression-free survival (hazard ratio = 0.48; P < .001) and overall survival (hazard ratio = 0.52; P = .002) than those with high count. This difference remained significant in multivariate analysis. Dynamic change of CTC count was significantly associated with partial response (P = .042) and stable disease/progressive disease (P = .032). Notably, dynamic monitoring of CTC provided evidence of resistance to EGFR-TKIs before computed tomographic scanning with a median lead time of 113 days (range, 45-169 days). CONCLUSION: The current evidence suggests that folate receptor-positive CTC counts can be used for both the dynamic monitoring and prediction of outcome in EGFR-mutated NSCLC patients treated with EGFR-TKIs, which could serve as an alternative or supplement to computed tomographic scanning.