Background: Patients with lung cancer with mutations in EGF receptor (EGFR) tyrosine kinase have improved prognosis whentreated with EGFR inhibitors.Wehypothesized that EGFR mutationsmaybe related to residential radon or passive tobacco smoke. Methods: This hypothesis was investigated by analyzing EGFR mutations in 70 lung tumors from a population of never and long-term former female smokers from Missouri with detailed exposure assessments. The relationship with passive smoking was also examined in never-smoking female lung cancer cases from the Mayo clinic. Results: Overall, the frequency ofEGFR mutation was 41% [95% confidence interval (CI), 32%-49%]. Neither radon nor passive-smoking exposure was consistently associated with EGFR mutations in lung tumors. Conclusions: The results suggest that EGFR mutations are common in female, never-smoking lung cancer cases from the United States, and EGFR mutations are unlikely due to exposure to radon or passive smoking.