The regulation of monocyte function and the inhibition of TNF-α production during bacterial sepsis are critical in attenuating adverse host responses to endotoxemia. To study the function of a novel receptor tyrosine kinase, mer, that is expressed in monocytes, we generated mice (mer kd) that lack the signaling tyrosine kinase domain. Upon LPS challenge, mer kd animals died of endotoxic shock (15/17, 88.2%), whereas control wild-type mice survived (1/15, 6.7% died). Susceptible mer kd mice exhibited edema, leukocyte infiltration, and signs of endotoxic shock that correlated with higher levels of TNF-α found in the serum of mer kd mice as compared with wild-type control animals. Death due to LPS-induced endotoxic shock in mer kd mice was blocked by administration of anti-TNF-α Ab, suggesting that overproduction of this cytokine was principally responsible for the heightened suseptibility. The increase in TNF-α production appeared to be the result of a substantial increase in the LPS-dependent activation of NF-κB nuclear translocation resulting in greater TNF-α production by macrophages from mer kd mice. Thus, Mer receptor tyrosine kinase signaling participates in a novel inhibitory pathway in macrophages important for regulating TNF-α secretion and attenuating endotoxic shock.