OBJECTIVES: This study aimed to assess the cost-effectiveness of ibrutinib vs. current frontline treatments for elderly/unfit patients with chronic lymphocytic leukemia (CLL), from a Belgian healthcare payer perspective. METHODS: A state transition model with three health states (progression-free survival [PFS], post-progression, and death) was used to capture ibrutinib’s benefits and costs over patient lifetime. Ibrutinib was compared to chlorambucil monotherapy; chlorambucil + obinutuzumab; bendamustine + rituximab; and physician’s choice (PC), a mix of the above treatments, as used in Belgian clinical practice. Data sources for efficacy outcomes included the RESONATE-2 trial (Burger et al. 2015) and results of a network meta-analysis which estimated treatments’ relative efficacy based on data from a systematic literature review (SLR). Long-term health outcomes were extrapolated based on trial data; utilities were based on EQ-5D-5L data collected in RESONATE-2 whenever possible, and supplemented by data identified in an SLR; Belgium-specific costs for drugs, administration, monitoring, resource use, and adverse events were used to estimate the incremental cost-effectiveness ratio (ICER). RESULTS: Ibrutinib showed incremental health gains of up to 7.13 life years (LYs) and 4.74 quality-adjusted LYs (QALYs). Ibrutinib was also associated with higher costs, largely driven by ibrutinib’s superior PFS, which led to longer time on treatment. The resulting ICER was €65,760/QALY gained versus PC and ranged between €51,641 and €76,451/QALY gained versus other comparators. The ICER versus PC was €42,540/LY gained and ranged from €34,361 to €49,424/LY gained versus other treatments. Sensitivity analyses showed that results were influenced by a few drivers, including discount rates for health and cost outcomes, and ibrutinib treatment duration. CONCLUSIONS: Results of our analysis indicate that ibrutinib offers a pronounced benefit over comparators for frontline CLL. ICERs are in line with general willingness-to-pay thresholds, demonstrating that ibrutinib represents a cost-effective use of resources for elderly/unfit frontline CLL patients.