Objectives: Immunity balance is regulated between immune activation and immune inhibition. Interleukin-12 (IL-12) has an essential role in the interaction between the innate and adaptive arms of immunity by regulating inflammatory responses, innate resistance to infection, and adaptive immunity. In addition, IL-12 is critical to an efficient host defense in polymicrobial sepsis. On the other hand, in response to inflammatory activation during LPS challenge, host cells also produce anti-inflammatory cytokines like interleukin-10 (IL-10). Imbalance between pro-inflammatory and anti-inflammatory response can result in circulatory failure, organ dysfunction, the immunosuppressive state and even death. Chlorella aqueous extract has been demonstrated to augment resistance against challenge with tumor cells in mice, which may be mediated through the participation of T cells and macrophages. However, immunomodulatory effects of Chlorella aqueous extract (doses between 2 and 0.25 mg/ml) were unknown. Methods: Effects of Chlorella aqueous extract on NO, TNF-α, and IL-10 productions and IL-12 gene expression in RAW264.7 macrophages were compared to LPS. Sepsis was induced by LPS (i.p.). Results and Conclusion: Although the level of NO production in Chlorella-treated cells was less than that obtained in LPS-stimulated cells, the production of TNF-α was comparable to LPS-stimulated group. The induction of IL-10 by Chlorella aqueous extract was greater than that seen in LPS-stimulated group. In addition, Chlorella aqueous extract (2 and 1 mg/ml) also enhanced IL-12p40 gene expression. LPS-induced significant mortality in mice, Chlorella aqueous extract (20 mg/kg) application improved the survival rate in the LPS-induced sepsis mice. Taken together, protective effects of Chlorella aqueous extract from LPS-induced sepsis may be mediated through counterbalance of anti-inflammatory cytokine IL-10 and proinflammatory cytokine IL-12 and TNF-α production.