The status of hyperreactivity and hyporeactivity following the administration of endotoxin in a susceptible host represents phenomena which are of interest in an attempt to understand the role of endotoxins in pathophysiological events in general. Two experimental approaches designed to examine these events are reported herein; i.v. injection with minute concentrations of endotoxin (10 ng of a BOIVIN endotoxin from E. coli 0111) induces tolerance against lethal doses of endotoxin (0.5 microgram or 5.0 microgram) within 24 h in hyperreactive NMRI mice that were infected 14 days before with BCG. Transfer of post-endotoxin serum from BCG infected mice, which contains a myriad of macrophage mediators and which induces nonspecific resistance to X-irradiation, renders a strain of mice (C3H/HeJ) that is hyporeactive to endotoxins, susceptible to the lethal effect of endotoxin. Studies of the role of the macrophage and its mediators in the experimental models described here may contribute to a further understanding of the mechanisms underlying endotoxin-induced biological activities.