Purpose In view of the promising results of a phase I trial, this phase II trial was conducted to study the efficacy and safety of intraarterial induction chemotherapy with a novel nanoparticle albumin–bound paclitaxel formulation in advanced head and neck cancer. Materials and Methods Sixty previously untreated patients with locally advanced squamous-cell carcinoma (SCC) of the oral cavity, oropharynx, or hypopharynx in stage T3/4 and any nodal stage received two to four cycles of nanoparticle albumin–bound paclitaxel by infusion into the external carotid artery or one of its branches, without premedication, at an initial dose of 230 mg/m 2 and subsequently a reduced dose of 150 mg/m 2. Response was evaluated by physical examination and multidetector computed tomography in all patients, and also by positron emission tomography with [ 18F]fluorodeoxyglucose in 38 patients. Definitive treatment was surgery, chemotherapy, radiation therapy, or chemoradiation therapy. Results Intraarterial chemotherapy had a low incidence of complications and produced complete or partial responses in 45 of 60 treated patients (75%). Seven patients (11.67%) had stable disease and eight (13.33%) had disease progression. High-grade bone marrow depression was rare. An unexpected toxicity was reversible facial nerve palsy on the side of infusion, which occurred in six patients at initial dosage. Reduction of the dose eliminated this specific toxicity without any loss of efficacy. Conclusion The promising response rates and tolerability of intraarterial chemotherapy with nanoparticle albumin–bound paclitaxel justify further investigation of this formulation, alone or in combination with other agents, in advanced SCC of the head and neck.