Introduction: Dengue virus (DENV), a mosquito-borne flavivirus, is a public health problem in Brazil and other tropical regions. Infection is characterized by a systemic inflammatory response and hematological alterations that may evolve with shock and death in severe cases. Chemokines and their receptors are important molecules involved in leukocyte recruitment and activation in many viral infections. Recent clinical data have shown an association between components of the chemokine network and severity of Dengue. However, the function of the chemokine system in the context of dengue infection is not known. Here we evaluated the role of CC chemokine receptors CCR1, CCR2, CCR4 and CCR5 in an experimental model of DENV-2 infection using mice genetically deficient for each chemokine receptor. Chemokine receptor antagonists were used to confirm major findings and evaluate potential therapeutic benefit of targeting the system. Methods: C57/BL6 (WT) and gene deficient mice were inoculated i.p. with 1 or 10 LD50 of a mouse adapted DENV-2 strain. Survival, MPO (as a marker of neutrophil accumulation), cytokines, histological analysis and viral titration in spleen and liver were evaluated. Hematocrit, platelet numbers and levels of cytokines and transaminases (TGO/TGP) were also evaluated in blood. Protocol CETEA/UFMG: 113/2009. Results: WT animals infected with DENV-2 died around day 7 after infection. At day 6, there was evidence of clinical disease and tissue damage, as shown by thrombocytopenia, hemoconcentration, increased levels of transaminases, neutrophil accumulation in tissues and elevated levels of cytokines (TNF-α, IFN-γ, IL-6, IL-12p40, CXCL1/KC). CCR1-/- mice were similar to WT mice with similar disease pattern and mortality, but slightly increased neutrophil accumulation and levels of IL-6, IFN- γ and KC in spleen, liver or serum. Lethality was decreased in CCR2-/- mice (p=0.03), tissue injury was slightly increased and systemic parameters of inflammation were similar to those of infected WT mice, although IFN- γ and IL-6 are reduced in liver. Infection enhanced levels of CCL17/TARC, a ligand for CCR4. More importantly, lethality rate, tissue injury and systemic inflammation were decreased in CCR4-/- mice. The phenotype of CCR5-/- mice was qualitatively similar to that of CCR4-/- mice but protection was much more pronounced in the former animals. Indeed, infected CCR5-/- mice did not die after infection and showed no hematological alterations or evidence of tissue injury or systemic inflammation. Importantly, viral load was greatly reduced in CCR5-/- mice (< 3 Log reduction). Finally, treatment with a CCR1/5 antagonist, MetRANTES (10 μg/mouse/day), was associated with decreased clinical disease, systemic inflammation and lethality after DENV-2 infection. Discussion: This study shows that the chemokine system plays a major role in the context of experimental dengue infection. Although CCR1 appears to play a minor role, CCR2 seems to be important for liver-associated pathology and CCR4 and CCR5 contributed markedly to tissue and systemic inflammatory changes associated with the experimental infection. CC chemokine receptor blockade, especially CCR5, may represent an interesting therapeutic approach for the treatment of dengue infection.