Background Evolving epidemiology and improvements in locoregional therapy necessitate reassessment of the relationship between locoregional failure and distant metastasis in squamous cell carcinoma of the head and neck (SCCHN). Methods Retrospective assessments of factors associated with distant metastasis-free survival were made for 560 patients with SCCHN who received definitive radiotherapy (RT) +/- concurrent systemic therapy at our institution between 1995 and 2007. Results Fifty-six patients (10.0%) developed distant metastasis. Three-year actuarial locoregional control and distant metastasis-free survival were 72% and 87%, respectively. Multivariate analysis revealed N classification and locoregional failure as significant predictors of reduced distant metastasis-free survival (p <.001). In patients with distant metastasis detected after locoregional failure, the mean interval between these events was 11.6 months. Conclusion Locoregional failure may play a causative role for distant metastasis in some patients with SCCHN, suggesting a need for continued focus on improving locoregional therapies. © 2012 Wiley Periodicals, Inc.