Suppressor of cytokine signaling (SOCS) 3 attenuates proinflammatory signaling mediated by the signal transducer and activator of transcription (STAT) family of proteins. But acute inflammation can occur after exposure to pathogen-derived inducers staphylococcal enterotoxin B (SEB) and lipopolysaccharide (LPS), or the lectin concanavalin A (ConA), suggesting that physiologic levels of SOCS3 are insufficient to stem proinflammatory signaling under pathogenic circumstances. To test this hypothesis, we developed recombinant cell-penetrating forms of SOCS3 (CP-SOCS3) for intracellular delivery to counteract SEB-, LPS- and ConA-induced inflammation. We found that CP-SOCS3 was distributed in multiple organs within 2 h and persisted for at least 8 h in leukocytes and lymphocytes. CP-SOCS3 protected animals from lethal effects of SEB and LPS by reducing production of inflammatory cytokines and attenuating liver apoptosis and hemorrhagic necrosis. It also reduced ConA-induced liver apoptosis. Thus, replenishing the intracellular stores of SOCS3 with CP-SOCS3 effectively suppresses the devastating effects of acute inflammation.