C-reactive protein (CRP) is an acute-phase protein produced by hepatocytes in response to infections and tissue damages. Although little has been known about its role in the innate immunity, we have recently reported that pretreatment with synthetic CRP rescues mice from lethal endotoxemia or E. coli infection by suppressing tumor necrosis factor-α (TNF) production but in turn enhancing phagocytic activity by Kupffer cells. In the present study, we assessed the influence of synthetic CRP on human immune system. Human peripheral blood mononuclear cells (PBMC) were stimulated in vitro by bacterial reagents, lipopolysaccharide (LPS), CpG-ODN and penicillin-treated streptococcus pyogenes (OK432) with or without synthetic CRP, and examined their cytokine production, antitumor responses. Synthetic CRP suppressed production of TNF and IL-12 but not interferon gamma (IFN-γ) from PBMC stimulated with bacterial reagents. Also, synthetic CRP upregulated the perforin expression of CD56+NK cells and increased antitumor cytotoxicity against Raji and K562 tumor cells. CRP may modulate macrophage to decrease production of inflammatory cytokines mediated by TLRs in human PBMCs but it may increase antitumor activity of NK cells, implying its therapeutic potential in human septic shock and cancers.