Objectives Xerostomia is a prevalent sequelae among nasopharyngeal cancer (NPC) survivors; yet, effective treatment protocols have been elusive. This study was a prospective randomized clinical trial to compare the effects of saliva substitute mouthwash in nasopharyngeal cancer survivors with xerostomia, between two treatment arms, conducted in a tertiary center. Materials and methods This study measured the effects within 4 weeks in relation to summated xerostomia inventory (SXI) and unstimulated whole saliva (UWS). Patients randomized into the interventional arm were prescribed an immunologically active saliva substitute (IASS), while patients in the control arm were prescribed a non-immunologically active mouthwash as placebo. Results The study population consisted of 94 patients. There was a significant difference in SXI difference (p < 0.0001) and UWS difference (p < 0.0001) between control and interventional arms. No harmful side effects associated with the use of either mouthwash encountered throughout the study duration. Conclusion IASS mouthwash significantly reduces subjective xerostomia scores measured using SXI and improves objective measurement of salivary flow using UWS among nasopharyngeal cancer survivors with xerostomia. Clinical relevance IASS is significantly more effective in improving subjective and objective xerostomia measurements compared to non-immunologically active mouthwash. Additionally, this treatment is very safe, with superior side effect profiles. Trial registration ClinicalTrials.gov Identifier: NCT04491435

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