Abstract INTRODUCTION Postoperative Cerebellar Mutism Syndrome (CMS) affects up to 25% of patients undergoing surgeries for posterior fossa (PF) tumors. There is no established treatment for CMS, although zolpidem has become widespread after reporting remarkable responses in some cases. However, there is very limited scientific evidence, prompting us to document our experience with zolpidem. OBJECTIVES To evaluate the efficacy and safety of zolpidem in patients with postoperative CMS in PF tumors. METHODS Observational, descriptive, retrospective study conducted at our institution. Patients <21 years diagnosed with CMS following PF tumor surgery between 2011-2023 and treated with zolpidem were included. Demographic and clinical data, therapies, CMS scales, and outcomes were collected. RESULTS Nineteen patients met the criteria, 84% males, median age 8 years (range, 9 months-19 years), and median follow-up time 30 months (range, 2-126). Diagnoses included 58% medulloblastoma, 21% pilocytic astrocytoma, 10.5% ependymoma, 10.5% others. CMS mutism scale was rated mild, moderate and severe in 5%, 21% and 74%, respectively. Median zolpidem administration was 31 days (range, 2-241) and median maximum dose was 0.25 mg/kg/day (range, 0.10-0.90). Mutism scores improved in 37% (7/19), 53% (8/15) and 64% (9/14) of patients that received zolpidem for at least 48h, 7 and 14 days, respectively. Subjective improvement in communication and interaction was observed in 74% (14/19). Only three patients with mild somnolence and one with initial irritability and insomnia were reported. CONCLUSIONS To our knowledge, this is the largest study of patients treated with zolpidem for CMS. A considerable proportion of children improved their language abilities within the first 24-48h, but some patients may even benefit from more prolonged treatment. Most children showed an adequate tolerance with very few side effects. Further studies are urgently needed, preferably within a randomized clinical trial, to find the real efficacy, appropriate dosage, and duration of zolpidem.