The administration of DTP vaccine has been shown to cause dose- and time-dependent alterations in hepatic drug metabolizing capacity in mice. Hexobarbital-induced sleep time was increased 12 hours after a single 0.5 ml injection of DTP vaccine, i.p., and reached a maximum increase of 2.5 fold 7 days after injection. This effect declined rapidly to levels not significantly different from controls by day 14. Spectrally assayed cytochrome P-450 levels were decreased by 50% for 7 days, as were specific microsomal monooxygenase activities. Cytosolic enzyme activities were also altered, but the time course was different from that of the microsomal enzyme activities. Endotoxin is a common component of many bacterial vaccines, and the effects of endotoxin administration on hepatic drug metabolism were assessed. Although endotoxin caused a dose-dependent increase in hexobarbital-induced sleep time, the time course of this effect was very different from that of the vaccines. The maximum increase in hexobartital-induced sleep time was observed 24 hours after a single injection of endotoxin, and returned to basal levels by 7 days. Other vaccines with high endotoxin content, such as typhoid and cholera vaccines, did not alter drug metabolism, while at least one viral vaccine with a low endotoxin content did alter hepatic drug metabolism. Thus, endotoxin may contribute to the toxicity, but it does not appear to be the sole component. Histologic examination of livers following administration of DTP vaccine indicated random multifocal areas of inflammation. Inflammatory cells were present only following administration of those vaccine preparations which altered hepatic drug metabolism. Fractionation of the pertussis vaccine has been undertaken to identify the component(s) involved in the toxic response. Studies are continuing to identify the components involved.