Although recent evidence suggests that myeloid clonal hematopoiesis (M-CH) may influence lymphoma clinical outcome, its impact in mantle cell lymphoma (MCL) remains unclear. Here, we report a comprehensive next-generation sequencing-based analysis of the M-CH mutational landscape at baseline and follow-up in patients enrolled in the Fondazione Italiana Linfomi MCL0208 phase 3 trial, evaluating lenalidomide maintenance vs observation after chemoimmunotherapy and autologous stem cell transplantation (ASCT) in untreated young patients with MCL. Overall, 254 of 300 (85%) enrolled patients (median age, 57 years [range, 32-66]) had a baseline sample available for CH analysis. Using stringent criteria, at least 1 mutation involving M-CH candidate genes was described in 34 patients (13%), with DNMT3A being the most frequently mutated gene (54%). After a median follow-up of 7 years, the presence of large CH clones (variant allele frequency of ≥10%) predicted worse progression-free survival (hazard ratio [HR], 2.93; 95% confidence interval [CI] 1.36-6.31; P = .006) and overall survival (HR, 3.02 [1.21-7.55]; P = .018) compared with patients with CH. Importantly, the competing risks analysis demonstrates that the worse clinical outcome associated with M-CH large clones is linked to MCL progression (P < .05). Moreover, large M-CH clones showed longer time to hematological recovery after ASCT than the remaining cohort (P = .026). In conclusion, we showed for the first time that large CH clones might associate with unfavorable clinical impact in patients with MCL. This trial was registered at www.clinicaltrialsregister.eu as EudraCT (2009-012807-25) and www.ClinicalTrials.gov as #NCT02354313.