Objective: To evaluate the reliability and validity of a new, disease-specific quality-of-life measure for patients with head and neck cancer: the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-QLQ-H&N35. Design: Cross-sectional study using questionnaire data and medical chart review. Setting: Academic tertiary care otolaryngology clinic. Participants: One hundred twenty ambulatory patients, including 30 patients with advanced head and neck cancer in each of the following stages of treatment: (1) prior to treatment, (2) during active treatment, (3) within 6 months of completing treatment, and (4) more than 6 months after completing treatment. In addition, (5) a comparison group of 40 patients without malignant disease was included (total sample, N = 160). Main Outcome Measures: Scores on EORTC Quality of Life Core Questionnaire (QLQ-C30) and head and neck module (QLQ-H&N35), Profile of Mood States, and Impact of Events Scale. Results: The QLQ-H&N35 demonstrated acceptable reliability (internal consistency). It successfully discriminated between cancer patients and the comparison group, and among subgroups of cancer patients at different phases of treatment (construct validity). The instrument was sensitive to the effects of radiation treatment and to site of disease. Its low-to-moderate correlations with the EORTC core questionnaire indicated that the QLQ-H&N35 provided unique information (discriminant validity). Scores were significantly associated with a number of demographic variables. Conclusion: Results support the use of this disease-specific measure to assess quality of life among patients with advanced head and neck cancer.