The objective of this study was to define the prognostic significance of surgical center case volume on outcome for head and neck cancer (HNC). Florida cancer registry and inpatient hospital data were queried for HNC diagnosed from 1998 to 2002. Of the 11,160 operative cases of HNC identified, 35.3% were treated at low-volume centers (LVCs), 32.7% in intermediate-volume centers (IVC), and 32.1% at high-volume centers (HVC). A larger proportion of high-grade tumors (27.9%) and lesions over 30 mm (39.7%) were resected at HVC (p < 0.001). Median survival was 61 months for HVC, 52 months for IVC, and 47 months for LVC (p < 0.001). Univariate analysis demonstrated significantly improved survival at HVC for low-, medium-, and high-grade tumors, small tumors (<30 mm), and for cancers of the parotid, larynx, and pharynx. On multivariate analysis, corrected for patient comorbidities, treatment at a HVC was a significant independent predictor of improved survival (HR = 1.25, p = 0.001). We conclude that HNC patients treated at HVC have significantly better long-term survival and cure rates. Where possible, patients with large (>30 mm), high-grade or parotid, larynx, and pharynx tumors should be evaluated and offered care at a high-volume center.