To examine the role of complement (C3) in determining the fate of lipopolysaccharide (LPS) in vivo, the distribution of LPS was studied in normocomplementemic (NC) and C3-depleted animals (pretreated with cobra venom factor [CoF]) after intravenous injection of highly purified, radioiodinated Salmonella minnesota R595 LPS. After injection of a lethal (250 micrograms) or nonlethal (5 micrograms) dose of LPS in NC and CoF rabbits and a lethal (5 mg/kg) dose of LPS in rhesus monkeys, the LPS disappeared from blood in a biphasic manner. In all cases, a substantial portion of the dose was removed from blood in an initial disappearance phase (t1/2 < 15 minutes), which, in some cases, was accelerated in CoF-treated animals. LPS remaining in blood beyond 30 minutes persisted with a much increased half-life (> 5 hours). Liver contained the major portion (40%) of tissue-bound LPS (determined by use of 131I-BSA blood marker) in animals killed 3--5 hours after injection. The distribution of LPS in rabbits was found to be dose-indpendent and only minimally changed by prior depletion of C3. In addition, the tissue distribution and cellular localization of LPS in monkeys was similar to that we have reported previously for R595 LPS in NC rabbits and was not substantially changed by prior CoF treatment. These results indicate that binding of C3 to intravenously injected LPS is not required for the initial rapid disappearance from blood. Further, the uptake of LPS by cellular targets, notably the hepatic macrophages (Kupffer cells), is not altered by in vivo decomplementation.