Background: the purpose of this study was to compare quality of life (QoL) and overall survival (OS) in patients with locally advanced head and neck cancer treated with radiotherapy only (RT), chemoradiotherapy with cisplatin (CT-RT) or RT with cetuximab (CET-RT). Methods: in this real-world, multi-institutional and prospective study, QoL outcomes were assessed using EORTC QLQ-C30 and QLQ-H&N43 questionnaires. Patients were treated according to each participating institution’s protocol. The Item Response Theory was used to generate a global QoL score, based on the 71 questions of both forms. Questionnaires were completed before treatment and every three months, thereafter. Survival was calculated using the Kaplan-Meyer method, and groups were compared by the log-rank test. The impact of the treatment modalities on QoL was analyzed using multivariate regression analyses. Results: Six hundred and twenty-six patients, with tumors located at the oral cavity (36%), oropharynx (30%), larynx (21%), hypopharynx (9%) and nasopharynx (4%) were included. Median follow up was 10.2 months. RT was delivered to 39% of the patients while 58% received CT-RT and 3% received CET-RT. Patients submitted to surgery were not included. OS was higher when systemic treatment was added to RT (median OS CET-RT: 21.9 months and CT-RT: 24.3 months, versus 14.2 months with RT, p < 0.05). A decrease in QoL during treatment was observed in all patients’ groups, but CT-RT had a statistically significant negative impact on QoL when compared to CET-RT (p = 0.02). An important limitation of the study is the low number of patients that received this last treatment modality, what is, probably, a result of local policies on reimbursement. Other factors that influenced QoL were alcohol consumption (better QoL for patients with no history of chronic alcohol consumption, p = 0.007) and radiotherapy technique (better QoL for patients treated with intensity-modulated RT, when compared to conformal RT, p < 0.001). Conclusions: We observed, as expected, better OS with systemic therapy, when associated to RT. A decrease in QoL was detected, as well, during treatment, but a less pronounced decrease was seen in patients receiving CET-RT, when compared to CT-RT. More studies are needed to confirm the QoL improvement in patients submitted to this last treatment approach.