Background and objective Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) has been widely used as the second- and third-line therapy in patients with advanced non-small cell lung cancer (NSCLC). However, its effect in the first-line treatment is unclear. The aim of this study was to evaluate the efficacy and safety of EGFRTKI as first-line therapy. Methods The clinical characteristics, responses rate, disease control rate and overall survival were retrospectively analyzed in 77 chemonaive patients with advanced NSCLC. All of the patients received oral gefitinib (250 mg/d) or erlotinib (150 mg/d) until disease progression or unacceptable toxicity occurrence. Results The overall response rate was 33.8% and the disease control rate was 68.8%. The median progression-free survival and the median survival time were 6.0 months and 8.9 months, respectively. One-year survival rate was 61.4%. Responses correlated significantly with histology, PS score, smoking history, skin rash, EGFR mutations and serum CEA. Histology and skin rash were the independent predictors of survival. Common toxicities were skin rash and mild diarrhea. EGFR-TKI could improve the clinical symptoms and the quality of life. Conclusion EGFR-TKI is effective and well tolerated as first-line therapy in patients with advanced NSCLC.