OBJECTIVES: Bendamustine and alemtuzumab are approved for treatment of chronic lymphocytic leukemia (CLL) in the US, and both are more expensive than chlorambucil. This analysis evaluated the cost-effectiveness of bendamustine (100 mg/m2/day intravenously, for 6 28-day cycles) vs. alemtuzumab (30 mg intravenously, for 12 weeks) vs. chlorambucil (0.8 mg/kg/day orally, for 12 cycles) in first-line treatment of CLL in the US. METHODS: The model was a discrete event simulation from a payer perspective, discounted at 3% annually with a lifetime horizon. Simulated patients were assigned baseline characteristics, treatment response, risk of adverse events, and infections based on data from 2 pivotal trials (Knauf et al, 2007; Knauf et al, 2009: bendamustine; Hillmen et al 2007: alemtuzumab) and supplemented by literature. Progression-free survival (PFS) and survival were predicted using survival functions derived from the bendamustine trial data. Resource use, costs (2009 US$), and utilities were from US databases and literature. RESULTS: The median PFS for bendamustine, alemtuzumab, and chlorambucil were 24, 15, and 11 months, respectively, and the total costs/patient were $75,243, $113,350, and $38,700, respectively. The incremental life years (LY) and quality-adjusted life years (QALYs) for bendamustine vs. chlorambucil were 0.89 and 0.72, respectively, resulting in incremental cost-effectiveness ratio (ICER) of $50,763/QALY. Bendamustine was dominant over alemtuzumab, i.e., the incremental LYs and QALYs for bendamustine were 0.73 and 0.57, respectively, at lower costs. Sensitivity analyses over a wide range of parameters indicated that bendamustine was dominant over alemtuzumab in all scenarios. The ICERs for bendamustine vs. chlorambucil ranged between $44,819 and $62,624/QALY. CONCLUSIONS: Treatment of CLL with bendamustine costs less and provides better health outcomes compared to alemtuzumab. Although bendamustine led to higher costs vs. chlorambucil, bendamustine was associated with an additional year of PFS, and the estimated ICER was within the acceptable, threshold commonly used in the US of $50,000–$100,000/QALY.