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Background: Malignant rhabdoid tumors (RT) are aggressive malignancies predominantly affecting very young children. The characteristic genetic alteration is the biallelic inactivation of SMARCB1. In approximately 30% of patients, one SMARCB1 allele is constitutionally altered conferring a particularly unfavorable prognosis. Constitutional mosaicism for pathogenic SMARCB1 mutations has recently been reported in distinct cases of allegedly sporadic RT. We aimed to systematically investigate the frequency and clinical impact of constitutional mosaicism in patients with sporadic RT included in the EU-RHAB registry., Methods: We selected 29 patients with RT displaying at least one pathogenic small variant in SMARCB1 in the tumor DNA and the absence of a germline mutation. We re-screened blood-derived patients and controlled DNA for the respective small variant by polymerase chain reaction with unique molecular identifiers and ultra-deep next-generation sequencing. Clinical data in patients with and without mosaicism and 174 EU-RHAB controls were compared., Results: Employing an ultra-deep sequencing approach, we detected tumor-associated SMARCB1 variants in blood-derived DNA in 9/29 patients. In 6/29 patients (21%), whose variant allele frequency (VAF) exceeded 2%, constitutional mosaicism was assumed whereas tumor DNA contamination was documented in 1/3 of patients with VAF below 1%. No significant differences were observed between 6 mosaic-positive and 20 -negative patients regarding age at diagnosis, presence of metastases, event-free or overall survival., Conclusions: Constitutional mosaicism for pathogenic small SMARCB1 variants is recurrent in patients with allegedly sporadic RT. The clinical implications of such variants need to be determined in larger, prospective cohorts also including detection of structural variants of SMARCB1., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)