IL-10 protects mice from lethal endotoxemia. IL-10 suppresses the production of IL-1, IL-6, and TNF-α in vitro, and neutralization of IL-10 in mice leads to increased levels of these monokines. This study tested whether IL-10's ability to suppress monokine production could protect mice from endotoxin-induced shock. A single injection of 0.5–1 μg of recombinant murine IL-10 protected BALB/c mice from a lethal intraperitoneal injection of endotoxin, whether administered concurrently or 30 minutes after endotoxin. The protective effect was reversed by prior injection of neutralizing anti-IL-10 antibodies and correlated with a decrease in endotoxin-induced TNF-α release. These findings suggest that IL-10 is a candidate for treating bacterial sepsis and as an effective anti-inflammatory agent. Severe bacterial infections can lead to septic shock, caused by endotoxin from gram-negative bacteria. Endotoxin-induced toxicity is due to the release of TNF-α and/or IL-1 from macrophages/monocytes. Neutralization of these monokines protects animals from shock. IL-10 is produced by various immune cells and suppresses monokine production, including TNF-α, IL-1α, IL-1β, IL-6, IL-8, and GM-CSF by monocytes and macrophages. In vivo experiments show that neutralizing IL-10 increases TNF-α and IL-6 levels. This study tested whether IL-10's ability to suppress TNF-α and IL-1, along with its ability to increase IL-1ra, makes it capable of protecting mice against endotoxin-induced shock. In experiments, groups of BALB/c mice were injected with LPS and varying amounts of IL-10. Mice were protected from death when 0.5, 1.0, or 10 μg of IL-10 was administered. Anti-IL-10 antibodies blocked this protection, confirming the specificity of the effect. IL-10 could also protect mice when administered 30 minutes after LPS injection. However, protection decreased with later administration. IL-10 reduced TNF-α levels in mice, suggesting that its protective effect is at least partially due to suppression of TNF-α. Other properties of IL-10, such as suppression of IL-1 production and upregulation of IL-1ra, may also contribute to its protective effect. These findings suggest that IL-10 is highly effective at protecting mice from lethal endotoxemia and may be an important candidate for treating bacterial sepsis.IL-10 protects mice from lethal endotoxemia. IL-10 suppresses the production of IL-1, IL-6, and TNF-α in vitro, and neutralization of IL-10 in mice leads to increased levels of these monokines. This study tested whether IL-10's ability to suppress monokine production could protect mice from endotoxin-induced shock. A single injection of 0.5–1 μg of recombinant murine IL-10 protected BALB/c mice from a lethal intraperitoneal injection of endotoxin, whether administered concurrently or 30 minutes after endotoxin. The protective effect was reversed by prior injection of neutralizing anti-IL-10 antibodies and correlated with a decrease in endotoxin-induced TNF-α release. These findings suggest that IL-10 is a candidate for treating bacterial sepsis and as an effective anti-inflammatory agent. Severe bacterial infections can lead to septic shock, caused by endotoxin from gram-negative bacteria. Endotoxin-induced toxicity is due to the release of TNF-α and/or IL-1 from macrophages/monocytes. Neutralization of these monokines protects animals from shock. IL-10 is produced by various immune cells and suppresses monokine production, including TNF-α, IL-1α, IL-1β, IL-6, IL-8, and GM-CSF by monocytes and macrophages. In vivo experiments show that neutralizing IL-10 increases TNF-α and IL-6 levels. This study tested whether IL-10's ability to suppress TNF-α and IL-1, along with its ability to increase IL-1ra, makes it capable of protecting mice against endotoxin-induced shock. In experiments, groups of BALB/c mice were injected with LPS and varying amounts of IL-10. Mice were protected from death when 0.5, 1.0, or 10 μg of IL-10 was administered. Anti-IL-10 antibodies blocked this protection, confirming the specificity of the effect. IL-10 could also protect mice when administered 30 minutes after LPS injection. However, protection decreased with later administration. IL-10 reduced TNF-α levels in mice, suggesting that its protective effect is at least partially due to suppression of TNF-α. Other properties of IL-10, such as suppression of IL-1 production and upregulation of IL-1ra, may also contribute to its protective effect. These findings suggest that IL-10 is highly effective at protecting mice from lethal endotoxemia and may be an important candidate for treating bacterial sepsis.