Introduction:: Erlotinib, a tyrosine kinase inhibitor, has improved survival and quality of life in patients with non-small cell lung cancer (NSCLC) after first- or second-line chemotherapy. Asian origin, adenocarcinoma histology, female gender, lack of tobacco use, and expression of epidermal growth factor receptor are significant independent predictors of response to Erlotinib. Although tobacco use is considered a major cause of NSCLC, other risk factors such as wood-smoke exposure (WSE) are associated. Almost 3 billion people worldwide rely on solid fuels as their primary source of domestic energy for cooking and heating. Methods:: In this study, 150 consecutive unselected patients with histologically proven NSCLC with progression after prior first- or second-line chemotherapy and/or poor performance status were treated with Erlotinib 150 mg/d. Clinical and pathologic characteristics were associated with response. Results:: Overall response to Erlotinib was observed in 51 patients [34%; 95% confidence interval {95% CI}, 29.9-37.6]. In multivariate analysis, clinical features associated with response to Erlotinib were adenocarcinoma (35 versus 20%; p = 0.05) and WSE (83 versus 13%; p < 0.001). Factors associated with longer progression-free survival in Cox analysis included adenocarcinoma (7.9 versus 2.3 months; p = 0.009), female gender (8.4 versus 5.3 months; p = 0.04), and WSE (17.6 versus 5.3 months; p = 0.006). Conclusions:: WSE is associated with better response to Erlotinib and improved progression-free survival in patients with NSCLC. Additional studies in epidermal growth factor receptor signaling pathway in WSE-associated NSCLC are warranted. Copyright © 2008 by the International Association for the Study of Lung.