Purpose The development of targeted therapy has introduced new options to improve treatment outcome in selected patients. The objective of this prospective study was to investigate the safety of preoperative erlotinib treatment and the (in vivo) response in patients with early-stage resectable non–small-cell lung cancer (NSCLC). Patients and Methods This study was designed as an open-label phase II trial, performed in four hospitals in the Netherlands, according to a Simon's minimax two-stage procedure. Initially, operable patients with early-stage NSCLC (n = 15) were entered from an enriched population (never-smoker, female sex, nonsquamous histology, or Asian ethnicity); thereafter, unselected patients were included to a total of N = 60. Patients received preoperative erlotinib 150 mg once daily for 3 weeks. Response to treatment was evaluated using [18F] fluorodeoxyglucose positron emission tomography (PET) and computed tomography (CT) scans during treatment and histologic examination of the resection specimen. Primary end points were toxicity and pathologic response. Results Sixty patients were included. Seven patients stopped treatment prematurely (12%). Skin toxicity was present in 37 patients (62%), and diarrhea was present in 21 patients (35%). PET evaluation revealed metabolic response (> 25% standardized uptake value decrease) in 16 patients (27%); CT evaluation using Response Evaluation Criteria in Solid Tumors (RECIST) showed response in three patients (5%). At surgery, no unexpected complications occurred. Pathologic examination showed more than 50% necrosis in 14 patients (23%), of whom three (5%) had more than 95% tumor necrosis. The response rate in the enriched population was 34% (10 of 29 patients). Conclusion According to predefined criteria, neoadjuvant erlotinib has low toxicity and sufficient activity to deserve further testing in future studies in an enriched population.