Sepsis is a dynamic disease, displaying an inflammatory profile that varies over time and for each organ. Controlling the inflammatory response based in targeting a single molecule has been proved useless. We hypothesized that treatment with bone marrow derived mononuclear cells (BMDMC) may be more efficient to modulate the systemic inflammatory response to infection. Adult male Balb/c mice were subjected to cecal ligation and puncture (CLP) or endotoxemia model of experimental sepsis. BMDMC were separated under Ficoll® gradient and injected intravenously 1 hour after the procedures. Cytokines concentration were quantified in plasma, lungs, heart and gut. Spleens, lymph nodes and thymus were used for lymphocytes isolation and cell death assessment. All measurements were performed 2 hours after BMDMC injection. RAW264.7 macrophages and BMDMC were co-cultivated in vitro to investigate the mechanisms involved. Our data showed that an early single intravenous injection of BMDMC in animals submitted to the murine model of endotoxemia led to: (1) improvement of survival rate; (2) BMDMC persistency in lung, liver and spleen after 24 hours; (3) decreased necrosis and apoptosis of mononuclear cells; (4) lower TNF-α, but increased IL-10 concentration in plasma and (5) tissue specific cytokine profile. In vitro experiments demonstrated that IL-6, IL-10 and nitric oxide production depends on direct contact of BMDMC to macrophages and that TNF-α production is negatively regulated by PGE2. BMDMC are efficient in protecting animals from endotoxemia and sepsis, reducing systemic inflammation as well as specifically modulating tissue inflammation, producing the necessary immune regulation to re-equilibrate the inflammatory response.