The aim of this study was to identify predictors of the Health-Related Quality of Life (HRQoL) in patients with head and neck cancers (HNCs). In total, 345 patients with HNCs were interviewed. A self-report questionnaire was administered to collect data about demographic characteristics, health status, smoking, alcohol consumption habits, and HRQoL. It were used the EORTC Instruments - Quality of Life Questionnaire-Core 30-questions (QLQ-C30), Quality of Life Questionnaire - Head and Neck Module 35-questions (QLQ-H&N 35) and OHIP-14 instrument for HRQoL assessments. Clinical information and treatment data were collected from medical records. Five groups of HRQoL predictors were identified: demographic, socioeconomic, behavioral, psychophysical, and clinical/treatment. These HRQoL predictors had a strong (i.e., age, level of social support and social contact, level of education, depression, fatigue, presence of gastrostomy, comorbidities, and use of pain medications and supplements), a moderate (i.e., marital status, smoking, sexuality problems, time since diagnosis, presence of tracheostomy, and side effects outcomes of radio and chemotherapy) and a small impact (i.e., employment/financial difficulties, tumor site and stage, and surgical procedure). Study identified nineteen predictors that had significant, moderate and small impact on the HRQoL of patients with HNCs. Some of the predictors, like levels of social support and social contact, depression, and comorbidities could be targets for innervations to improve HRQoL.