Background. Identifying patients with head and neck cancer at greatest risk of poor health-related quality of life (HRQOL) will facilitate screening for such patients and targeted interventions. Methods. This was a cross-sectional, self-administered survey with medical record review among 65 out-patients with head and neck cancer >6 months from diagnosis and off treatment. Results. Most were men (80%) and white (95%), with a mean age of 60 ± 13 years. The most prevalent cancer type was squamous cell (88%), site was pharyngeal (40%), and stage was III or IV (80%). Lower total HRQOL was independently associated with gastrostomy (p < .001) and history of radiation therapy (p < .05)(R2 = 0.27). Certain HRQOL subscales were also independently associated with depression, body mass index, age, and education. Conclusions. Several factors can be used to identify patients with head and neck cancer at risk for persistent reductions in HRQOL requiring intervention. © 2009 Wiley Periodicals, Inc.