The purpose of this study was to evaluate associations between germline epidermal growth factor receptor (EGFR) variants involved in transcriptional regulation and overall survival in white patients with non‐small‐cell lung cancer (NSCLC) treated with the EGFR tyrosine kinase inhibitor, gefitinib. Of 175 consecutive patients treated with oral gefitinib (250 mg/day), 170 (median age: 67 years; 72% men) were evaluable for genotyping and survival. Fifty‐five patients (33%) had stable disease and 17 (10%) had an objective response. The most common of four haplotypes was G‐C (EGFR*1) at the EGFR −216G>T and −191C>A loci (frequency, 0.45). After adjusting for performance status, previous platinum‐containing chemotherapy and occurrence of skin rash or diarrhea during the first treatment cycle in patients with performance status 0 or 1 (N=139), the absence of EGFR*1 was associated with significantly better survival (hazard ratio: 0.54; 95% confidence interval: 0.32–0.91; P=0.015). The results may help identify patients with NSCLC who can benefit from gefitinib treatment. Clinical Pharmacology & Therapeutics (2008) 83, 3, 477–484.doi:10.1038/sj.clpt.6100320