This prospective study was done to validate an earlier retrospective study demonstrating a relationship between complete response to chemotherapy and nodal density as estimated in contrasted computed tomography (CT scans) in head and neck squamous cell carcinoma (HNSCC). CT scans of 36 patients were evaluated by two radiologists blinded to therapeutic outcome. The density of the largest node (> 2 cm) was compared to that of nuchal muscles. A node was classified as hypodense if more than 33% of the nodal surface area consisted of hypodense zones. Density and nodal staging were related: 67% (10 of 15) of patients with N3 disease but only 29% (six of 21) with N1-N2 exhibited isodensity, p < 0.05. Complete response to chemotherapy was noted in 63% (10 of 16) of the isodense group but only in 15% (three of 20) of the hypodense group, p < 0.01. We believe that nodal density can be used for therapeutic decision-making in high nodal volume HNSCC.