Purpose Mantle-cell lymphoma (MCL) is an incurable mature B-cell neoplasm with high initial response rates followed almost invariably by relapse. Prognosis for patients following relapse is poor, and treatment choices are limited. We evaluated the efficacy and safety of zanubrutinib, an investigational selective Bruton's tyrosine kinase (BTK) inhibitor. Patients and Methods Patients with relapsed/refractory MCL were enrolled in this ongoing phase 2, single-arm, open-label study and treated with oral zanubrutinib 160 mg twice daily. The primary endpoint is overall response rate (ORR) assessed by an independent review committee (per Lugano 2014 classification); secondary endpoints include duration of response (DOR), time to response, progression-free survival (PFS), and safety. Results Eighty-six patients (median age, 60.5 years) were enrolled after a median of 2 prior lines of therapy, received ≥1 dose of the study drug, and were evaluable for safety and efficacy. After a median follow-up of 18.4 months, 72 (84%) patients achieved an objective response, with 59 (68.6%) achieving a complete response (CR). Median DOR and PFS were 19.5 and 22.1 months, respectively; 12-month event-free estimates for DOR and PFS are 78% and 76%, respectively. Most common grade ≥3 adverse events (AEs) were neutropenia (19.8%) and lung infection/pneumonia (9.3%). Three patients experienced major bleeding events, and there were no reports of atrial fibrillation. Eight (9.3%) patients discontinued zanubrutinib for AEs. Conclusion These results demonstrate high and durable ORR and CR rates in patients with relapsed/refractory MCL. Zanubrutinib was generally well-tolerated; grade ≥3 BTK inhibitor-associated toxicities (hemorrhage, rash, hypertension, diarrhea, atrial fibrillation) were uncommon. Copyright ©2020, American Association for Cancer Research.