Abstract Background Information is scarce regarding the impact of treatment on Health-Related Quality of Life (HRQL) of patients with Head and Neck (H&N) cancers. We assessed the effect of treatment on HRQL and its association with prognosis in H&N cancer. Patients and Methods Patients with H&N cancer in whom HRQL was assessed before and after treatment. The European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 and QLQ-H&N35 instruments were used. Association of changes in patients’ HRQL after treatment with Loco-Regional Recurrence (LRR) and Overall Survival (OS) was investigated. Results One hundred sixty patients were included; scales of the baseline assessment of HRQL were moderately associated with LRR and OS, but the impact of treatment on most HRQL scales was strongly associated with OS. By multivariate analysis, baseline assessment of Global Health, Physical, HN Teeth, HN Dry mouth, and HN Cough scales, and impact of treatment on the Physical and Pain scales comprised independent variables associated with LRR. Male gender, positive lymph nodes, baseline assessment of Role, HN Pain, HN Cough, and impact of treatment on Emotion, Pain, Financial, HN Swallowing, HN Social contact, and the interaction of HN Pain-change in Pain scales were associated with OS. Both multivariate models were adjusted by the neoplasm’s site of origin. Conclusion Aside from well-known clinical-pathologic prognostic factors in H&N cancers, HRQL assessment, both prior to and after treatment, provides significant prognostic information and should be measured. Design of therapeutic clinical trials in patients with H&N cancers should consider these novel prognostic factors.