2009 Background: Little is known about the relationship between the pharmacokinetics and efficacy of gefitinib. METHODS Plasma trough levels of gefitinib were measured on days 0, 3 (D3), and 8 (D8) by HPLC in advanced NSCLC patients treated with gefitinib 250 mg daily. Eligibility criteria included: performance status (PS) ≤ 3, age ≤ 80, stage IIIB-IV, and written informed consent. RESULTS Fifty patients were enrolled, and 44 patients were assessable. The median [25%-75%] values of D3 and D8 was 662 [440-937] and 1064 [782-1405] ng/ml, respectively. D8/D3 rate was categorized by 1.587 of the median value. In 44 patients, the median time to progression (TTP) was 83 days, and the median overall survival (OS) was 224 days. The differences in TTP were compared by Kaplan-Meier method and log-rank test: D8/D3 (high D8/D3, median 209 days vs. low D8/D3, 43 days; P = 0.0299), smoking (never-smokers, 224 days vs. smokers, 32 days; P = 0.0467), and histology (adenocarcinoma, 97 days vs. non-adenocarcinoma, 27 days; P = 0.0096). Sex, age, PS, previous treatments, and the use of antacids were not significant. Multivariate analysis showed that TTP was associated with D8/D3 (hazard rate, 95%CI; 0.458, 0.234-0.898) and smoking (2.005, 1.030-3.903). Never-smokers with high D8/D3 showed the best TTP, and smokers with low D8/D3 showed the worst TTP. Never-smokers with low D8/D3 and smokers with high D8/D3 showed similar TTP curves. In contrast, OS was associated with smoking (hazard rate, 95%CI; 3.182, 1.506-6.724), but not D8/D3. CONCLUSIONS High D8/D3 was independently associated with better TTP in gefitinib-treated NSCLC patients. Our findings suggest that pharmacokinetics of gefitinib may be involved in its anti-tumor activity. No significant financial relationships to disclose.