Erlotinib, a potent inhibitor of the tyrosine-kinase (TK) activity of human epidermal growth factor receptor (HER1/EGFR), produces significant survival and quality of life benefits in patients with previously treated advanced-stage non-small-cell lung cancer. Although the survival benefit from erlotinib was observed in varied subgroups of patients, the radiographic responses were more common in certain patient subgroups, such as women, never-smokers, patients with adenocarcinoma histology, patients of Asian ethnicity, and patients with presence of HER1/EGFR TK domain mutations. Herein, we describe a white male former smoker with advancedstage squamous cell non-small-cell lung cancer, who responded to first-line erlotinib. A molecular analysis of the tumor did not reveal HER1/EGFR TK mutations. This case study, along with subgroup analyses of the BR.21 phase III study, suggests that patients should not be selected for erlotinib treatment based only on characteristics, such as smoking status, tumor histology, HER1/EGFR TK mutation status, sex, or ethnicity.