Intravenous injection of negatively and positively charged liposomes containing entrapped poly(I)-poly(C) induced a vigorous interferon response in mice with serum titers of interferon reaching twenty times those observed with comparable dosages of free poly(I)-poly(C). The response did not persist over an extended time period as observed earlier for enhanced interferon production stimulated by positively charged liposomes containing the inducer. Both negatively and positively charged liposomes containing [14C]poly(I)-poly(C) were taken up chiefly by the liver when given intravenously. Negatively charged particles were concentrated somewhat preferentially by the spleen (7--9% of the dose compared to 4--6%). Less radioactivity was found in liver and spleen when negatively charged particles were given intraperitoneally than was the case when positively charged particles were injected by this route. Free [14C]poly(I)-poly(C) was extensively metabolized to low molecular weight materials within four hours of injection, while encapsulation of the polymer provided protection against in vivo degradation. When both preferential localization and protection were considered, from three to five times as much high molecular weight E114C]poly(I)-poly(C) was recovered from liver at four hours after intravenous injection when the compound was given in encapsulated form compared to free polymer. Similarly, for spleen, seven times and three times as much polymeric [14C]poly(I)-poly(C) was recovered following injection of negatively charged liposomes and positively charged liposomes respectively compared to free [14C]poly(I)-poly(C). At 48 h after an intravenous injection of positively charged liposomes, as much as four percent of the dose remained in high molecular weight form in the liver and one percent in the spleen. Following intraperitoneal injections, polymeric [14C]poly(I)-poly(C) recovered from the liver never exceeded 4.3% of the dose, showing that most of the radioactivity in the liver consisted of metabolites. These results suggest that elevated and prolonged production of interferon in animals treated with encapsulated inducer results from a combination of factors including preferential tissue location and protection of the inducer from hydrolytic cleavage.