Injection of Salmonella typhosa endotoxin into either CF1 or C57bl/6J mice leads to prompt increases in serum colony-stimulating factor (CSF). Repeated injections of endotoxin result in a dose-related hyporesponsiveness or tolerance to this effect. Tolerance is seen after either intravenous (i.v.) or intraperitoneal (i.p.) routes of administration or challenge and occurs after one to two preinjections. Cross-tolerance to heterologous endotoxin (Escherichia coli) was also shown. This cross-tolerance is complete immediately after cessation of preinjections, but partial at later time intervals. Levels of a serum inhibitor of colony growth were decreased in tolerant mice, although this decrease is not statistically significant. Tolerant mice injected with endotoxin release granulocytes from the bone marrow normally, in spite of the absence of a CSF response. This suggests that neutrophil releasing activity (NRA) and CSF are separate entities. A marked marrow granulocytic hyperplasia develops after 7 or 20 days of endotoxin injections, despite the tolerance to the CDF-elevating effect of endotoxin. This granulocytic hyperplasia could still be mediated by serum CSF increases. A negative medullary feed-back secondary to the repetitive release of marrow granulocytes, however, is an equally plausible mechanism for the stimulation of granulocyte production. It is also possible that the decrease in serum inhibitors played a role in the sustained increase in granulopoiesis seen here.