Background: While the efficacy and safety of zanubrutinib have been established in relapsed or refractory chronic lymphocytic leukemia, the evidence on cost effectiveness is still lacking.Objective: We aimed to evaluate the cost effectiveness of zanubrutinib versus ibrutinib in relapsed or refractory chronic lymphocytic leukemia from the commercial payer perspective in the USA.Methods: A partitioned survival model was developed based on survival curves from the phase III ALPINE trial. We reconstructed patient-level data for each curve and conducted a parametric estimation to incorporate long-term clinical outcomes and treatment costs into the model. Medical costs and utilities were obtained from public data and previous cost-effectiveness studies. A discount rate of 3.0% per annum was applied and costs were adjusted to 2023 US dollars. The incremental cost-effectiveness ratio was calculated by dividing the incremental costs of zanubrutinib over ibrutinib by the incremental life-years or quality-adjusted life-years. Deterministic and probabilistic sensitivity analyses were performed to examine the robustness of the results.Results: Over a 10-year analysis period, the incremental cost-effectiveness ratio of zanubrutinib versus ibrutinib was $91,260 per life-year gained and $120,634 per quality-adjusted life-year gained, making it cost effective within a threshold of $150,000 per quality-adjusted life-year gained. The incremental cost-effectiveness ratio was most sensitive to drug acquisition costs and progression-free survival distributions, and the probability of zanubrutinib being cost effective was approximately 52.8%, with a 30.0% likelihood of dominance.Conclusions: Zanubrutinib is likely to be cost effective versus ibrutinib in relapsed or refractory chronic lymphocytic leukemia in the USA, but the high threshold should be noted. Our findings may provide a basis for pricing strategy and reimbursement decisions for zanubrutinib.