Activated macrophages play an important role in many inflammatory diseases. However, the molecular mechanisms controlling macrophage activation are not completely understood. Here we report that a novel CCCH zinc finger protein family MCPIP1, 2, 3 and 4, encoded by four genes Zc3h12a, Zc3h12b, Zc3h12c and Zc3h12d respectively, regulates macrophage activation. Northern blot analysis revealed that the expression of MCPIP1 and MCPIP3 were highly induced in macrophages in response to treatment with lipopolysaccharide (LPS). Although not affect cell surface marker expression and phagocytotic function, overexpression of MCPIP1 significantly blunted LPS-induced inflammatory cytokine and NO2- production as well as their gene expression. Conversely, short interfering RNA-mediated reduction in MCPIP1 augmented LPS-induced inflammatory gene expression. Further studies demonstrated that MCPIP1 did not directly affect the mRNA stability of tumor necrosis factor a (TNFa) and monocyte chemoattractant protein 1 (MCP-1), but strongly inhibited LPS-induced TNFa and inducible nitric oxide synthase (iNOS) promoter activation. Moreover, we found that forced expression of MCPIP1 significantly inhibited LPS-induced nuclear factor (NF)-B activation. These results identify MCPIPs, a novel CCCH zinc finger protein family, as negative regulators in macrophage activation and may implicate in host immunity and inflammatory diseases.