This article examined the cost-effectiveness of zanubrutinib and ibrutinib for managing relapsed and refractory chronic lymphocytic leukemia from the viewpoint of payers in China and the US.Markov models were employed to conduct comparisons. Baseline characteristics and clinical data were extracted from the ALPINE study. The cost-effectiveness outcome indicators encompassed cost, quality-adjusted life years, and the incremental cost-effectiveness ratio.The Markov model analysis revealed that the zanubrutinib group incurred an incremental cost per patient of $-24,586.53 compared to the ibrutinib group. The zanubrutinib group exhibited an incremental utility per capita of 0.28 quality-adjusted life years, resulting in an incremental cost-effectiveness ratio of $-88,068.16 per quality-adjusted life year, which is lower than the payment threshold in China. The willingness-to-pay value in China for 2022 was three times the country's gross domestic product per capita. In the US, patients in the zanubrutinib group experienced per capita incremental costs of $-79,421.56, per capita incremental utility of 0.28 quality-adjusted life years, and an incremental cost-effectiveness ratio of $-284,485.45 per quality-adjusted life year.For Chinese payers, zanubrutinib exhibited superior cost-effectiveness compared to ibrutinib. Zanubrutinib proved to be a more affordable option for US payers when considering the payment threshold.