Purpose: Surgical treatment of malignancies in the oral cavity and subsequent radiotherapy often result in an oral condition unfavorable for prosthodontic rehabilitation. This study assessed the quality of life related to oral function in edentulous head and neck cancer patients following oncology treatment of malignancies in the lower region of the oral cavity. Materials and Methods: Patients treated between 1990 and 2000 with surgery and radiotherapy for a squamous cell carcinoma in the oral cavity who were edentulous in the mandible and had been treated with a conventional, non-implant-retained denture received an invitation for a clinical check-up (clinical assessment, questionnaires regarding oral function and quality of life). Results: Sixty-seven of the 84 patients who fulfilled the inclusion criteria were willing to participate in the study. The mean irradiation dosage that these patients had received in the oral region was 61.8 ± 5.4 Gy. Half of the patients (n = 33) were not very satisfied with their prostheses; they wore their mandibular prostheses at most a few hours per day. It was concluded from the clinical assessment that two thirds of the patients (n = 44) could benefit from an implant-retained mandibular denture. Analyses of the questionnaires revealed no significant associations between functional assessments, quality of life, and parameters such as size of the primary tumor, location of the primary tumor, and different treatment regimes. Despite cancer treatment, the patients reported a rather good general quality of life. Conclusions: Sequelae resulting from radiotherapy probably dominate oral function and quality of life after oncology treatment. In two thirds of the patients, improvement of oral function and related quality of life would be expected with the use of an implant-retained mandibular denture.