BACKGROUND. Quality-of-life instruments that measure specific functional consequences of mucositis are needed to assess the efficacy of therapeutic interventions targeted against mucositis and to guide patient care. The authors undertook a prospective, multicenter, observational study to assess the validity, reliability, and feasibility of a new instrument, the Oral Mucositis Weekly Questionnaire-Head and Neck Cancer (OMWQ-HN). The OMWQ-HN is a patient-reported outcome questionnaire that measures the symptoms of mucositis, including mouth and throat soreness (MTS), and their impact on patient well-being and function. METHODS. The OMWQ-HN, along with the Functional Assessment of Cancer Therapy-Head and Neck (FACT-HN), was administered 5 times over an approximately 6-week period to patients with head and neck cancer (HNC) who were receiving radiation therapy with or without chemotherapy. Information on supportive care measures also was collected. RESULTS. Seventy-five patients were enrolled and completed 93% of scheduled assessments (100% at baseline). The OMWQ-HN demonstrated good test-retest reliability (correlation coefficient, 0.80-0.89). Cross-sectional analyses to assess validity showed that OMWQ-HN scores were different across levels of pain, with those in the worst pain category reporting the highest OMWQ-HN scores. Strong correlations were observed between OMWQ-HN and FACT-HN. Patients experienced increases in MTS, which corresponded with a steady decline in function. MTS scores were highest in the patients who were taking opioid analgesics, suggesting that mucositis pain continued despite standard pain therapy. CONCLUSIONS. The current results indicated that the OMWQ-HN is a valid, reliable, and feasible instrument for assessing the impact of mucositis on patients who are receiving radiation therapy with or without chemotherapy for HNC. © 2007 American Cancer Society.