Background: Available preclinical and phase 2 clinical data suggest that the addition of cetuximab, a monoclonal antibody directed against the epidermal growth factor receptor (EGFR), to chemotherapy might improve outcome in patients with advanced non-small-cell lung cancer (NSCLC). We aimed to assess whether the addition of cetuximab to chemotherapy improved progression-free survival in patients with recurrent or progressive NSCLC after platinum-based therapy. Methods: In this unmasked, open-label randomised phase 3 trial we enrolled patients with metastatic, unresectable, or locally advanced NSCLC from 121 sites in Canada and the USA. Eligible patients were those aged 18 years or older who had experienced progressive disease during or after one previous platinum-based regimen. Initially, patients were randomly assigned to receive either pemetrexed (500 mg/m2) or docetaxel (75 mg/m2) and then randomly assigned within each group to receive their chemotherapy with or without cetuximab (400 mg/m2 at first dose and 250 mg/m2 weekly thereafter) until disease progression or unacceptable toxicity. However, after a change in the standard of care, investigators chose whether to treat with pemetrexed or docetaxel on a patient-by-patient basis. The primary analysis was changed to compare progression-free survival with cetuximab plus pemetrexed versus pemetrexed, on an intention-to-treat basis. This study is registered with ClinicalTrials.gov, number NCT00095199. Findings: Between Jan 10, 2005, and Feb 10, 2010, we enrolled 939 patients; data for one patient was accidentally discarded. Of the remaining 938 patients, 605 received pemetrexed (301 patients with cetuximab and 304 alone) and 333 received docetaxel (167 in combination with cetuximab and 166 alone). Median progression-free survival with cetuximab plus pemetrexed was 2·9 months (95% CI 2·7-3·2) versus 2·8 months (2·5-3·3) with pemetrexed (HR 1·03, 95% CI 0·87-1·21; p=0·76). The most common grade 3-4 adverse events with cetuximab plus pemetrexed were fatigue (33 [11%] of 292 patients), acneiform rash (31 [11%]), dyspnoea (29 [10%]), and decreased neutrophil count (28 [10%]), and with pemetrexed alone were dyspnoea (35 [12%] of 289 patients), decreased neutrophil count (26 [9%]), and fatigue (23 [8%]). A significantly higher proportion of patients in the cetuximab plus pemetrexed group (119 [41%] of 292 patients) experienced at least one serious adverse event than those patients in the pemetrexed group (85 [29%] of 289 patients; p=0·0054). Nine (3%) of 292 treated patients in the cetuximab and pemetrexed group died of adverse events compared with five (2%) of 289 treated patients in the pemetrexed alone group. Interpretation: The use of cetuximab is not recommended in combination with chemotherapy in patients previously treated with platinum-based therapy. Funding: Eli Lilly and Company and ImClone Systems LLC, a wholly owned subsidiary of Eli Lilly and Company. © 2013 Elsevier Ltd.