This study evaluates the changes in quality of life (QoL) from pre-treatment to 3 years after commencement of treatment and its relation to therapeutic variables in patients with oral and oropharyngeal carcinoma. QoL was assessed using the EORTC QLQ-C30 questionnaires and the EORTC head and neck cancer specific module QLQ-H&N35. QoL data were obtained prior to treatment and 1 and 3 years after treatment began. Of 128 patients, 69 completed all the questionnaires over the course of 3 years. Variable deterioration of QoL scores was detected before treatment. Most of the parameters worsened significantly after treatment and during the first year, and improved by the third year. Patients who underwent surgical treatment combined with adjuvant radiotherapy and chemotherapy generally showed worse scores and needed a long time to recover from the disease and the treatment adverse effects. This long-term prospective study performed using the EORCT questionnaires in a homogeneous group of patients with oral and oropharyngeal carcinoma may allow better understanding of the impact of treatment and the changes in QoL that occur.