Background and objective Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have become first-line treatment drugs for lung adenocarcinoma patients with EGFR gene mutations. Significant interindividual variations in response rate, progression-free survival (PFS), and overall survival (OS) have been observed. The expression level of nuclear factor erythroid-2-related factor 2 (Nrf2) is related to chemoresistance against platinum drugs. Nrf2 overexpression can inhibit the sensitivity of EGFR-TKIs in cells with EGFR-sensitive mutations. The aim of this study is to investigate the protein expression level of Nrf2 in lung adenocarcinoma patients with EGFR gene mutations and to elucidate the correlation between Nrf2 expression and response rate of first-line EGFR-TKIs, as well as PFS and OS. Methods Immunohistochemical analysis of Nrf2 in tumor specimens was performed on 31 patients with stage III or IV adenocarcinoma harboring EGFR gene mutations. Results The Nrf2-positive rate was 77.4%, whereas Nrf2 nuclear high-expression rate was 38.7%. The nuclear expression level of Nrf2 was significantly correlated with response rate (RR) and PFS of EGFR-TKIs (P<0.05), but not with gender, age, smoking, differentiation, and OS (P>0.05). The Nrf2-positive level was significantly correlated with PFS and OS of EGFR-TKIs (P<0.05), but not with gender, age, smoking, differentiation, EGFR gene mutation status, and RR (P>0.05). The PFS and OS of patients with Nrf2-positive expression were significantly shorter than those in patients with negative expression (P<0.05). Furthermore, the nuclear expression level of Nrf2 was the independent predictive factor for EGFR-TKI-induced PFS, and the Nrf2-positive level was the independent predictive factor for EGFR-TKI-induced OS (P<0.05). Conclusion The expression level of Nrf2 is significantly correlated with response rate (RR) of EGFR-TKIs, PFS, and OS. Therefore, Nrf2 may be a useful biomarker in predicting response of EGFR-TKIs in patients with advanced-stage lung adenocarcinoma harboring EGFR gene mutations.