The clearance and localization of native DNA, denatured DNA, and double-stranded synthetic RNA was studied in New Zealand Black/White hybrid mice, which develop an illness closely resembling human systemic lupus erythematosus, and in normal mice. The three nucleic acids were rapidly cleared from the circulation in all strains studied. Serum nucleases did not account for this rapid clearance, indicating that the nucleic acids were taken up as macromolecules. The polymers were concentrated in the liver and spleen, suggesting uptake by the reticulo-endothelial system. Animals with circulating antibody cleared the nucleic acids even more rapidly. New Zealand mice did not differ from normal mice in their metabolism of nucleic acids.