Abstract: Objective: To analyze the relationship between EGFR (HER1), HER2, and HER3 protein expression and to determine their utility as predictive markers for response to gefitinib (Iressa) therapy in advanced non- small- cell lung cancer (NSCLC) patients. Methods: From May 2002 to February 2005, NSCLC patients who failed to respond to at least one platinum- based regimen received 250 mg of gefitinib once daily, until disease progression or intolerable toxicity occurred. EGFR, HER2, and HER3 protein expression in tumors from these patients was detected using immunohistochemistry. Results: EGFR, HER2, and HER3 expression was detected in 90 patients with positive rates of 16.7%,43.3% and 21.1%, respectively. EGFR and HER3 expression were not correlated with curative effect,but treatment efficacy in HER2 positive patients was significantly higher than that in those without HER2 expression (35.9% vs. 15.7%, P=0.027). Compared with HER2 and HER3 negative patients,HER2 and HER3 positive patients have a significantly better response (53.8% vs. 22.1%, P= 0.036).The median time to tumor progression (TTP) was 4.0 months; and median overall survival time (OS) was 11.5 months. EGFR, HER2, and HER3 expression status was not correlated with the TTP or OS. Conclusions: Among advanced NSCLC patients, there was no correlation between the EGFR status and cu-rative effect, TTP and OS. Patients with positive expression of both HER2 and HER3 have a better response than those without, regardless of the EGFR expression status.