BACKGROUND: No treatments are presently available to increase survival in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck after failure of platinum-based chemotherapy. We aimed to assess efficacy and safety of zalutumumab, a human IgG1 monoclonal antibody targeting the epidermal growth factor receptor, for overall survival in such patients. METHODS: In our open-label, parallel-group, phase 3, randomised trial, we randomly allocated patients with squamous-cell carcinoma of the head and neck who were regarded as incurable with standard therapy, a WHO performance status of 0-2, and progressive disease within 6 months of platinum-based therapy in a 2:1 ratio to receive zalutumumab plus best supportive care (zalutumumab group) or best supportive care with optional methotrexate (control group) at medical centres in Europe, Brazil, and Canada. Randomisation was done via a centralised interactive voice-response system, stratified by performance status. Data were analysed when the randomisation code was broken, after the completion of the accrual and cleaning of the relevant data. An independent review committee, masked to treatment assignment, assessed tumour response and disease progression according to response evaluation criteria in solid tumours. Zalutumumab was given weekly by individual dose titration on the basis of skin rash. After a prespecified 231 deaths, we included all randomised patients in the survival analyses and all patients receiving at least one session of therapy in the safety analysis. The primary endpoint was overall survival, although progression-free survival was also assessed. This trial is registered with ClinicalTrials.gov, NCT00382031. FINDINGS: We randomly allocated 191 (67%) of 286 eligible patients to the zalutumumab group and 95 (33%) to the control group. Median overall survival was 6.7 months (95% CI 5.8-7.0) in the zalutumumab group and 5.2 months (4.1-6.4) in the control group (hazard ratio [HR] for death, stratified by WHO performance status, was 0.77, 97.06% CI 0.57-1.05; unadjusted p=0.0648). Progression-free survival was longer in the zalutumumab group than in the control group (HR for progression or death, stratified by WHO performance status, was 0.63, 95% CI 0.47-0.84; p=0.0012). 189 patients given zalutumumab and 94 controls were included in the safety analysis. The most common grade 3-4 adverse events were rash (39 [21%] patients in the zalutumumab group vs none in the control group), anaemia (11 [6%] vs five [5%]), and pneumonia (nine [5%] vs two [2%]). 28 (15%) patients in the zalutumumab group had grade 3/4 infections compared with eight (9%) in the control group. The most common serious adverse events were tumour haemorrhage (28 [15%] patients given zalutumumab vs 13 [14%] controls), pneumonia (13 [7%] vs three [3%]), and dysphagia (11 [6%] vs two [2%]). INTERPRETATION: Although zalutumumab did not increase overall survival, progression-free survival was extended in patients with recurrent squamous-cell carcinoma of the head and neck who had failed platinum-based chemotherapy. Zalutumumab dose titration on the basis of rash is safe. FUNDING: Genmab.