Background: Platinum-based chemotherapy with cetuximab is the standard of care for relapsed or metastatic squamous cell carcinoma of the head and neck (SCCHN). The aim of this trial was to investigate whether cetuximab and paclitaxel/carboplatin can achieve similar progression free survival (PFS) with less toxicity compared to standard cetuximab and 5-FU/platinum based chemotherapy. Methods: In this multicentre, randomised, controlled, phase 2 trial, 85 patients with relapsed or metastatic SCCHN were randomised in a 1:1 ratio to cetuximab and 5-FU/cisplatin or carboplatin (arm A, n = 42), versus cetuximab and paclitaxel/carboplatin (arm B, n = 43). Patients without disease progression continued with cetuximab maintenance every second week until progression or toxicity. Eligibility criteria included age ≥18 years, Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0–1, and adequate organ functions. The primary endpoint was to investigate whether PFS in arm B is non-inferior to PFS in arm A using a liberal non-inferiority margin of 1.5 for the PFS hazard ratio (HR). Results: The median age for the whole study population was 60.9 years with a male predominance (69.4%). Clinically significant parameters, such as tumour localization, tumour stage, PS, HPV status and age were well balanced between the two treatment arms. Adverse events ≥ grade 3 were more frequent in arm A than in arm B (60% vs 40%; p = 0.034). Median PFS in arm A was 4.37 months (95% CI: 2.9- 5.9 m) and 6.5 months (95% CI: 4.8-8.2 m) in arm B, (p = 0.064). Median overall survival (OS) was 8.4 months (95% CI: 5.3-11.5 m) in arm A and 10.2 months (95% CI: 5.4-15 m) in arm B (HR = 0.71; 95% CI: 0.43-1.16). PFS HR for arm B was 0.65 (95% CI: 0.41- 1.03) and the predefined non-inferiority criterion was met. Conclusions: Cetuximab and paclitaxel/carboplatin was found to have similar efficacy and less toxicity compared to cetuximab and 5-FU/cisplatin or carboplatin. The experimental arm is easier to administer rendering it a favourable alternative to standard therapy in daily clinical practice. Clinical trial information: NCT01830556