Background: This trial investigated the efficacy and safety of weekly cetuximab combined with two different schedules of paclitaxel/ carboplatin for stage IIIB/IV non-small-cell lung cancer (NSCLC). Methods: A total of 168 patients with previously untreated stage IIIB/IV NSCLC were randomized to arm A, cetuximab (400 mg/m2 day 1 followed by weekly 250 mg/m2) + paclitaxel (Taxol) (225 mg/m2)/carboplatin (AUC6) day 1 every 3 weeks or arm B, same cetuximab regimen plus paclitaxel (100 mg/m2) days 1, 8, and 15 every 3 weeks and carboplatin (AUC6) day 1 every 4 weeks. Treatment continued for a four-cycle maximum. Patients with a complete response, partial response, or stable disease after four cycles could receive cetuximab 250 mg/m2/week until disease progression or unacceptable toxicity. The primary end point was to evaluate progression-free survival (PFS). Results: Median PFS was 4.7 and 4.3 months for arms A and B, respectively (6-month PFS, 27.3% versus 30.9%). Median overall survival was 11.4 versus 9.8 months for arms A and B, respectively; estimated 1-year survival, 47.7% versus 39.3%; and objective response rate, 29.6% versus 25%. The regimen was well tolerated with rash and hematologic toxicity being most common. Conclusions: This study did not meet the prespecified benchmark of 35% 6-month PFS rate; both combination schedules of cetuximab plus paclitaxel/carboplatin were feasible and equivalent for treating advanced NSCLC. © The Author 2009. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.