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Hairy cell leukemia variant (HCL-v) is a rare B-cell malignancy with limited treatment options in relapsed or refractory settings. We describe the first reported case of chemo-refractory HCL-v successfully treated with zanubrutinib monotherapy. An 84-year-old man, previously refractory to rituximab and bendamustine, achieved early hematologic improvement and reduction in spleen size after starting zanubrutinib, with a sustained clinical and laboratory response at 17 months. A clinical study with ibrutinib has shown durable disease control in classic and variant HCL, supporting BTK inhibition as a therapeutic strategy. This case suggests zanubrutinib as a promising chemo-free option for frail HCL-v patients.