PURPOSE: The long-term effect of adipose-derived mesenchymal stromal cells (ASC) on restoring radiation-induced salivary gland hypofunction in patients with previous head and neck cancer has not been validated in larger settings. PATIENTS AND METHODS: The study was a 12-month follow-up of a randomized trial, including patients with hyposalivation. Patients were randomized to receive allogeneic ASC or placebo in the submandibular glands. The primary endpoint was unstimulated whole saliva (UWS) followed by stimulated whole saliva, patient-reported outcomes (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire, Head and Neck Module, and the xerostomia questionnaire), and safety. RESULTS: Of the 120 enrolled patients, 117 (97.5%) were assessed at 12 months. Treatment with ASC did not increase UWS compared with placebo: Increase in UWS was 0.02 mL/minute [95% confidence interval (CI), 0.01-0.04] in the ASC group and 0.02 mL/minute (95% CI, 0-0.03) in the placebo group (P = 0.56). ASC reduced the symptom burden for dry mouth with -10.07 units (95% CI, -13.39 to -6.75) compared with -4.15 units (95% CI, -7.46 to -0.84) in the placebo group (P = 0.01). Compared with placebo, ASC did not improve sticky saliva (-9.27 vs. -4.55 units
P = 0.13), swallowing (-4.50 vs. 3.49 units
P = 0.5), or xerostomia (-3.12 vs. -2.74 units
P = 0.82). Treatment was safe and associated with a transient immune response. CONCLUSIONS: Intraglandular ACS therapy in the submandibular glands significantly relieved subjective dry mouth symptoms. Both ASC and placebo increased UWS, but ASC did not prove superior to placebo in restoring salivary gland function, based on the salivary flow rate.