Background: The standard of care for first-line treatment of recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN) is combination treatment with cisplatin, 5-FU and cetuximab (PFE). However, this regimen requires hospitalization to ensure proper hydration and continuous infusion of 5-FU, and causes severe nausea and anorexia. We evaluated the efficacy and safety of paclitaxel, carboplatin and cetuximab (PCE) as first-line treatment in patients with R/M SCCHN. Methods: Eligibility included recurrent and/or metastatic, histologically proven SCC of the oropharynx, oral cavity, hypopharynx or larynx; PS 0-1; adequate organ function; no suitable local therapy for R/M SCCHN; and no prior systemic chemotherapy for R/M SCCHN. Chemotherapy consisted of paclitaxel 100mg/m² on day 1, 8; carboplatin AUC 2.5 on day 1, 8, repeated every 3 weeks for up to 6 cycles; and cetuximab at an initial dose of 400mg/m², followed by 250mg/m²weekly until disease progression or unacceptable toxicities. Primary endpoint was overall response rate (ORR). Secondary endpoints were safety, treatment completion rate, progression-free survival, overall survival, and clinical benefit rate (CBR). Planned sample size was 45 patients. Results: Forty-seven subjects were accrued from July 2013 and Oct 2014. Of 45 evaluable, 40 were male; median age was 63 years; ECOG PS was 0/1 in 23/22 cases; site was the hypopharynx/oropharynx/oral cavity/larynx in 17/11/10/7 cases; and 36/9 cases were smokers/non-smokers, respectively. ORR was 37.8% (95% CI 30.9–48.6). Median overall survival was 14.7 months (95% CI, 12.1–Not Reached) and progression-free survival was 5.2 months (95% CI 3.9–5.6). Grade 3 or 4 adverse events included neutropenia (68%), skin reaction (15%), fatigue (9%) and febrile neutropenia (9%). A potentially treatment-related death occurred in one patient with intestinal pneumonia. Conclusions: The PCE regimen shows promising activity with acceptable toxicity and can be provided in the outpatient clinic. Further studies are needed to compare PCE with PFE in this population. Clinical trial information: UMIN000010507.