The specific aim of this study was to assess the relationship between the mutation status of the epidermal growth factor receptor (EGFR) gene and excision repair cross-complementation group 1 (ERCC1) in lung adenocarcinoma of patients that received platinum-based neoadjuvant chemotherapy. One hundred and seven primary lung adenocarcinoma patients with 22 stage IIa, 61 stage IIb, and 24 stage IIIa (TNM staging 2009) were included in this study. EGFR genetic mutations including exon 19 and 21 were detected by direct polymerase chain reaction (PCR) sequencing and compared with various clinical/pathologic features. Immunohistochemistry was performed to detect the expression of ERCC1 compared to EGFR mutation status in tumors. The frequency of EGFR mutations before and after chemotherapy was 64.3% (61/107) and 73.2% (70/107), respectively. The mutation frequency of exon 19 and 21 were 60.7% (37/61) and 39.3% (24/61) prior to chemotherapy, compared to 58.6% (41/70) and 41.4% (29/70) after chemotherapy. Mutations in EGFR were significantly different in females (prechemo: p = 0.003 vs. postchemo: p = 0.012) and nonsmokers (prechemo: p = 0.007 vs. postchemo: p = 0.000). Positive expression of ERCC1 was higher in patients with unchanged EGFR mutation status (28.4%, 25/88) than that in patients with altered mutation status (26.3%, 5/19) (p = 0.021). Log rank analysis indicated that disease-free survival was influenced by EGFR mutation status. Patients with an unchanged EGFR mutational status after chemotherapy were more likely to express ERCC1, and this change may serve as a clinical indicator of therapy response.