Detection of EGFR mutations is indispensable to determine appropriate lung cancer treatment. Although 70% of lung cancer patients with EGFR activating/sensitive mutations benefit from EGFR tyrosine kinase inhibitor (EGFR-TKI), they eventually acquire resistance. Re-treatment with EGFR-TKI often produces long survival for advanced lung cancer patients. However, it has yet to be elucidated what subpopulation of patients is amenable to re-challenge with EGFR-TKI. We have sought a non-invasive monitoring system for EGFR mutation status using circulating plasma DNA and have established novel methods to identify EGFR mutations: wild inhibiting PCR and quenched probe system (WIP-QP) for exon 19 deletions and mutation-biased PCR and quenched probe system (MBP-QP) for L858R. These detection systems include fully automated genotyping based on the analysis of the probe DNA melting curve, which binds the target mutated site using a fluorescent guanine quenched probe (QP-system) combined with MBP or WIP to achieve higher sensitivity. Detection limit was 0.005-0.04 ng in genomic DNA and 0.1–0.3% with mutant plasmids. DNA isolated from lung cancer specimens and circulating plasma DNA samples of 39 adenocarcinoma patients whose primary tumors harbored EGFR exon 19 deletions or L858R were examined. Results in cancer tissue specimens were identical to those based on existing systems [nucleic acid-locked nucleic acid PCR clamp (PCR clamp) or cycleave PCR], except that two samples evidenced both exon 19 deletions and L858R. Using plasma DNA, exon 19 deletions and L858R were detected in 44.7 and 8.7% of patients, respectively. Serial monitoring of exon19 deletion and L858R demonstrated correlations with the disease state. These monitoring systems are simple, sensitive and, intriguingly, reflective of the clinical course, which can be applicable for deciding lung cancer treatment.