Background: Factors affecting the patient's voice and Quality of Life (QOL) by means of Persian Voice Handicap Index (VHI) are important in non-laryngeal Head and Neck Cancers (HNCs) following (chemo)radiation therapy. This study aimed to investigate the vocal problems caused by (chemo)radiation therapy among Iranian patients with non-laryngeal HNCs and to evaluate the factors affecting the patient's voice QOL by means of Persian VHI. Material and Methods: Seventy patients with non-laryngeal Head and Neck Cancers (HNCs) were treated by radiation therapy, and eighty individuals with normal voice were considered. Acoustic analysis and self-assessment with the Persian VHI questionnaire were performed before, during, and 6 months after the treatment. Normal subjects were tested once. Changes in the acoustic parameters and VHI questionnaire scores over the time and their correlation was assessed using statistical analysis. The effect of important factors on the patient's voice and QOL in different groups was investigated. Results: The results showed that the acoustic parameters except mean F0, and questionnaire data deteriorated significantly (P < 0.001) during the treatment and improved at the final assessment, but not to the initial level. There was a significant relationship between some of the acoustic parameters and subgroups of the VHI questionnaire at the end and 6 months after treatment. Chemotherapy, mean laryngeal dose and smoking were factors that affecting the patient's QOL. Conclusions: Radiation dose in non-laryngeal tumor in HNCs causes laryngeal damage and vocal problems. Acoustic analysis and Persian VHI questionnaire were two valuable methods in evaluating the patients' voice and QOL. Radiation dose, chemotherapy and smoking greatly impact the aggravation of vocal problems.