OBJECTIVES: To evaluate the cost-effectiveness of biological treatments in first line for unfit patients with chronic lymphocytic leukemia in the Colombian context. METHODS: A cost-effectiveness analysis using a Markov model was conducted adopting the perspective of a third party payer (Colombian health care system) and making a comparison among the biological therapies authorized in Colombia: obinutuzumab (also known as GA101) plus chlorambucil (G-Clb), rituximab plus chlorambucil (R-Clb) and rituximab plus bendamustine. Time horizon was 10 years, with monthly cycles. Three health states were considered, progression free survival (PFS), disease progression (DP), and death. This model assessed two primary outcomes: Quality Adjusted Life Years (QALYs) and Life Years gained (LYg). Transition probabilities, utilities and frequency of adverse events were obtained from published randomized clinical trials. Direct costs included were estimated from official national databases (in December 2015 Colombian pesos, exchange rate used 1 USD=3062 COP). RESULTS: For the 10-years time horizon, G-Clb improved the clinical outcomes (QALYs and LYg) in comparison with R-Clb and R-Bend. The incremental cost-effectiveness ratios (ICERs) for GClb vs RClb was USD 17763,6 and for GClb vs R-Bend was USD -22313,4 (GClb generates cost-saving).  CONCLUSIONS: Compared with R-Clb and R-Bend, obinutuzumab plus chlorambucil is the most cost-effective biological therapy and is associated with better clinical outcomes in unfit patients with previously untreated Chronic Lymphocytic Leukemia in the Colombian context.