OBJECTIVE The aim of this study was to assess the clinical usefulness of cetuximab and cisplatin alone or in combination with paclitaxel as the first-line treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC). METHODS Three hundred patients with confirmed HNSCC from 20 different hospitals were included in this study. Patients in group I underwent a 2-hour infusion of 400 mg/m2 cetuximab (day 1), followed by a 1-hour infusion of 250 mg/m2 cetuximab weekly and 1-hour infusion of 100 mg/m2 cisplatin (days 1 and 21) per treatment cycle. Patients in group II were treated with a combination of cetuximab, cisplatin, and paclitaxel. Patients received 6 cycles of 175 mg/m2 paclitaxel given on days 1 and 21. The primary outcome of the study was progression-free survival (PFS); overall survival (OS) and objective response rate (ORR) were the secondary endpoints. RESULTS The median PFS was 5 months and 8 months for patients in groups I and II, respectively (HR, 0.93; 95% CI, 0.85-1.78; P > 0.05). Similarly, we found no significant differences in OS between the 2 groups (median OS, 13 vs. 11 months, respectively; HR, 0.67; 95% CI, 0.42-1.43; P = 0.198). Moreover, we observed no significant difference in ORR between the 2 groups (ORR, 63.3% vs 69.9%, respectively; HR, 0.87; 95% CI, 0.36-1.67; P = 0.231). CONCLUSIONS The combination of paclitaxel with cetuximab and cisplatin did not improve patient outcomes compared to cetuximab plus cisplatin alone. Therefore, the 2-drug regimen could be used as first-line treatment in patients with recurrent or metastatic HNSCC.