Radiotherapy is the standard treatment of head and neck cancer (HNC). The radiation may affect on surrounding normal tissue and salivary gland resulting to xerostomia. Treatment of post-radiation-related xerostomia focuses on relieving symptoms by using saliva substitutes or saliva stimulants. Because the salivary stimulants have significant side effects, such as sweating, dizziness or increasing urge to urinate, saliva substitutes are preferable. Saliva substitute has been suggested to improve moisture in dry mouth condition. The form of saliva substitutes may be in oral gel or oral rinse. However, patients complained of the thick consistency of the solution. The purpose of this study is to evaluate the effectiveness and patient’s satisfaction of carboxymethylcellulose (CMC) oral spray to improve dry mouth condition and quality of life (QoL) in post-radiotherapy patients. Thirty-five post-radiotherapy patients diagnosed with HNC were included to use CMC oral spray. Patients were interviewed with a Xerostomia-related Quality of Life score (XeQoLs) questionnaire and collected saliva, then instructed to use spray for two pumps (approximately 0.4 ml.), 4 times a day, after 3 meals and before bedtime. After 14 days of use, all participants were interviewed with the questionnaire and collected saliva again. Patients significantly had better XeQoLs scores after use of CMC oral spray in the aspect of physical, pain/discomfort, and psychological dimensions (P<0.05) but not social dimension (P>0.05). Salivary pH and saliva volume were increased after use, but not statistically significant. The results suggested that CMC oral spray can effectively relieve subjective symptom of oral dryness with adequate patients’ satisfaction leading to improve QoL in post-radiated period for HNC patients.