Intraperitoneal injection of mice with mineral oil, incomplete (IFA) or complete Freund's adjuvant (CFA) increased the interferon response to endotoxin or (poly rI)-(poly rC) administered intravenously 2 days later. After endotoxin administration, circulating interferon titers were increased at several different times of sampling and with a variety of endotoxin dosages. When injection of endotoxin was delayed until 6 to 8 days after the administration of IFA or CFA, interferon production was markedly decreased. Mice treated with CFA and injected with endotoxin 2 days later became more resistant to intranasal vesicular stomatitis virus challenge than mice injected with endotoxin alone. Hyporeactivity to the interferon-inducing capacity of a second injection of endotoxin 2 days after the first injection could not be overcome by administering CFA simultaneously with the first dose. CFA treatment not only raised the serum interferon titers produced by endotoxin, but also increased the number of interferon-forming cells in the spleen after administration of endotoxin in vivo. In addition, CFA enhanced the intravascular clearance of (poly rI) * (poly rC). The possibility that Freund's adjuvant increased the interferon response to endotoxin and (poly rI) * (poly rC) by stimulating the uptake and processing of the interferon inducer by lymphoreticular cells is discussed. The interferon response to endotoxin can be increased by several factors such as preinfection with attenuated tubercle bacilli (BCG; references 41 and 42), X-ray irradiation (11), adrenalectomy (11, 28), lead acetate (W. R. Stinebring and M. Absher, Proc. Int. Symp. Interferon, Lyons, in press), cycloheximide (40, 43, 45), and zymosan [a cell wall extract from Saccharomyces cerevisiae (Y. Nagano and N. Maehara, Japan-U.S.A. Interferon Seminar, Tokyo, in press)]. Some of these factors (BCG, zymosan) have also been reported to stimulate the phagocytic activity of the reticuloendothelial system (5, 30) and to have an adjuvant effect on antibody formation (6, 14). Other factors such as kinetin riboside, thorotrast, corticoids, cyclophosphamide, and cytotoxic drugs have suppressing effects on both antibody and interferon production (as reviewed by E. De Clercq and T. C. Merigan, Annu. Rev. Med., in press). 'Fellow of the Damon Runyon Memorial Fund for Cancer Research, "Aangesteld Navorser" of the Belgian N.F.W.O. (Nationaal Fonds voor Wetenschappelijk Onderzoek).