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Genetic and microenvironmental factors leading to aberrant activation of the NF\u2010\u03baB pathway have been implicated in SMZL pathogenesis. CYLD is a negative regulator of NF\u2010\u03baB and other signaling pathways acting as a deubiquitinase of regulatory molecules and has been reported as a tumor suppressor in different types of cancer, including B\u2010cell malignancies. To assess whether CYLD is implicated in the natural history of SMZL, we profiled primary cells from patients with SMZL and SMZL cell lines for CYLD expression and functionality. We report that CYLD is downregulated in patients with SMZL and that <jats:italic>CYLD<\/jats:italic> ablation in vitro leads to NF\u2010\u03baB pathway hyperactivation, promoting the proliferation of SMZL cells. In addition, we found that CYLD deficiency was associated with increased migration of SMZL cells in vitro, through CCR7 receptor signaling, and with increased dissemination in vivo. <jats:italic>CYLD<\/jats:italic> loss was sufficient to induce BcR signaling, conferring increased resistance to ibrutinib treatment in vitro. In summary, our work uncovers a novel role of CYLD as a key regulator in SMZL pathogenesis, dissemination, and resistance to targeted agents. 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