OBJECTIVES: Febrile neutropenia (FN) is a common side effect of systemic chemotherapy associated with significant morbidity, mortality, detrimental quality of life and high costs. Most FN events occur in the first cycle. Guidelines recommend the prophylactic use of a recombinant human granulocyte colony-stimulating factor (G-CSF) in patients receiving chemotherapy if risk of FN ≥20%. We aimed to assess the cost-effectiveness of different G-CSF primary prophylactic regimens in Mexico. METHODS: A decision model allowed comparison of expected costs and outcomes after three competing interventions as prophylaxis: Pegfilgrastim 6mg once (PegFGT); filgrastim 300μg daily during 6 days (FGT-6d) or 3 days (FGT-3d). Time-horizon was 21 days (i.e., first cycle). Direct medical costs comprising acquisition of G-CSF plus ambulatory/inpatient medical care derived from FN were analyzed under the perspective of Mexican public health system and expressed in 2015 dollars (USD). Clinical outcomes included frequency of FN events and deaths attributable to FN. Published literature and indirect treatment comparisons were used for estimating the effectiveness for each intervention. Costs parameters were based on local sources. Deterministic and probabilistic sensitivity analyses were conducted. RESULTS: PegFGT was the least costly strategy (USD$1,473) leading to overall savings of USD$103 (6.6%) and USD$327 (18.2%) when compared to FGT-6d and FGT-3d, respectively. The expected number of FN events and deaths caused by FN were also lower with PegFGT (99; 11) than with FGT-6d (241; 26) or FGT-3d (285; 31), leading to a lower cost of treatment. Based on the cost-effectiveness results, PegFGT was the least costly option in around 89% of the simulations generated through probabilistic sensitivity analysis. CONCLUSIONS: A single dose of pegfilgrastim given instead of administering daily doses of filgrastim for 3 or 6 days leads to better health outcomes and cost-savings when used as prophylaxis of FN in patients with solid tumors or lymphoma receiving chemotherapy.