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Quality of life (QOL) has become an important aspect of today's health care management. This study performed longitudinal assessment of QOL in patients with advanced cancers of the buccal mucosa (T4). We compared the QOL between patients who received adjuvant chemoradiation therapy (CTRT) and that of patients who received radiation therapy alone and assessed whether baseline QOL can predict disease recurrence.This was a prospective study of 225 patients with T4 buccal mucosal cancer. Health-related QOL was assessed at baseline and at 3, 6, 9, and 12 months after completion of treatment by means of the European Organization for Research and Treatment of Cancer Core QOL Questionnaire and the HN35 questionnaire.There was persistent improvement in global QOL and pain. Emotional functioning improved at 12 months. Most of the head and neck–specific symptoms deteriorated at 3 months, with subsequent improvement at 12 months except in swallowing, senses, speech, social eating, social contact, and sexuality. Patients who received adjuvant CTRT had poorer QOL. Poorer baseline global QOL (P = .049), dyspnea (P = .04), appetite loss (P = .015), and weight loss (P = .08) may predict recurrence.Although there is an improvement in global QOL and pain, most of the head and neck–specific symptoms worsened in the immediate postoperative period. Adjuvant CTRT has a persistent effect on specific domains compared with adjuvant radiation therapy alone. Poor baseline QOL scores are associated with a higher risk of recurrence.