OBJECTIVES  This study aimed to estimate the cost-effectiveness of Ofatumumab plus Chlorambucil (OChl) compared with Chlorambucil (Chl) for patients with Chronic Lymphocytic Leukemia for whom fludarabine-based therapies are considered inappropriate, from the perspective of the publicly funded health care system in Canada. METHODS A semi-Markov based decision model was developed with a lifetime time horizon. The model comprised two distinct phases. The preprogression phase was based on the overall response rates (ORR), progression free survival (PFS) and overall survival (OS) observed in the COMPLEMENT-1 trial.  The postprogression phase was based on Canadian treatment practices, treatment patterns identified in clinical guidelines and published literature. The incremental cost per quality-adjusted life year (QALY) gained was computed using model-estimated first- and subsequent-line treatment costs, general disease management costs, and QALYs based on health-state preference utility weights. RESULTS  The discounted, lifetime health and economic outcomes estimated by the model showed that first-line treatment with OChl in comparison with Chl in the target population led to an increase in QALYs (0.41) and an increase in total costs (CAD $27,850), resulting in an incremental cost-effectiveness ratio (ICER) of CAD $68,672/QALY gained. Various scenario analyses indicated that the cost-effectiveness results were sensitive to the time horizon, the method used to assess response, and the extrapolation of OS treatment effect beyond the trial period. One way and probabilistic sensitivity analyses aligned with the results of the base-case analysis. CONCLUSIONS The base-case results indicate that the improved ORR, PFS, and OS for OChl in comparison with Chl translate to improved long-term health outcomes. The analysis found that the ICER for OChl versus Chl in the target population was CAD $68,672/QALY gained. A variety of sensitivity and scenario analyses confirmed that the model’s cost-effectiveness estimates were robust.