Xerostomia is one of the one complications following radiotherapy that can affect quality of life (QoL). This study aims to assess the severity of xerostomia in patients with head and neck cancers after radiotherapy and its effect on QoL. In this longitudinal prospective study, the severity of xerostomia and related QoL were was assessed in 63 head and neck cancer patients who referred to the Radiotherapy Ward. Patients completed a xerostomia questionnaire (XQ) at the beginning, and 2, 4, and 6 weeks after treatment over a period of 6 months. Additionally, unstimulated saliva was collected using the spitting method at all 4 visits. QoL significantly worsened with increased time (P = 0.0001); meanwhile, the severity of xerostomia increased significantly (P = 0.0001). However, there was no significant change in the amount of saliva at these 4 time points (P = 0.23). Regression analysis showed that with each milliliter decrease in saliva secretion, the QoL score decreased 2.25%. With one score increase in xerostomia, from the QoL mean score there was a 1.65% decrease. The decrease in saliva and xerostomia that resulted from radiotherapy plays an important role in worsening QoL among patients who undergo radiotherapy for head and neck cancers. Although the amount of saliva has a significant association with QoL, the xerostomia score which shows subjects' general feeling also independently impacts QoL. In future studies, we recommend patient assessments for periods longer than 6 months.