Background The purpose of this investigation was to present 5‐years of quality‐of‐life (QOL) results of a multicenter randomized phase III trial, assessing intra‐arterial (IA) versus standard intravenous (IV) chemoradiation for inoperable stage IV head and neck cancer. Methods Evaluation of 71 patients through European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core Module (EORTC QLQ‐C30) and Head and Neck Module (QLQ‐H&N35), and trial‐specific questionnaires. Treatment consisted of standard radiotherapy with 4 weekly IA or 3 weekly IV cisplatin infusions. Results No significant differences in treatment‐related QOL problems between 1 and 5 years posttreatment were observed, except for “dry mouth” (gradually improving; p = .004). Survivors have lower fatigue levels (p = .04), better voice (p = 0.3), and swallowing (p = .03) than patients who could not complete all subsequent follow‐up questionnaires. Conclusions Most treatment‐related QOL issues deteriorate during treatment, improve in the first year, and then remain stable, except xerostomia, improving up to the 5‐year assessment point. Survivors show more positive scores for fatigue, voice, and swallowing. QOL issues at 1 year, thus, for most already represent those after 5‐year follow‐up. © 2011 Wiley Periodicals, Inc. Head Neck, 2012