Oncological treatment of head and neck carcinoma is associated with high morbidity. Measuring of health-related quality of life (HRQoL) is crucial in this patient group but there is no consensus on which measure would be preferable to be used. In this study, HRQoL was measured with the generic 15D, which has not been used before for assessing this patient population. It is a prospective cohort study among 64 patients with laryngeal, pharyngeal or nasal cavity carcinoma treated with definitive (chemo) radiotherapy between November 2007-July 2012. HRQoL was assessed with the 15D before and at 3, 6 and 12 months after the treatment onset. HRQoL results of the patients were compared with those of the age-standardized general population. Overall HRQoL declined significantly during the first 3 months after the treatment onset but then gradually improved towards the end of the follow-up. At baseline or at 12 months, no significant differences were detected in overall HRQoL between the patients and the general population. Dimensions reflecting mental well-being showed gradual improvement, exceeding the baseline scores at the end of the follow-up. Nevertheless, on these dimensions, the patient group presented with consistently lower scores compared with the general population. The mean HRQoL was lower among patients with pharyngeal carcinoma compared with the laryngeal carcinoma patients. The 15D instrument is feasible for evaluation of HRQoL in oncologically treated head and neck cancer patients. It seems to detect differences among different patient subgroups. Multidisciplinary supportive management of this patient population is recommended to ensure improved mental well-being.