Clearance of exogenous ssDNA from circulation was rapid and occurred primarily through the liver. With higher doses of single-stranded DNA (ssDNA), both liver uptake and whole blood clearance approached a maximum, enabling larger amounts of ssDNA to persist in the circulation. The large molecular weight material (precipitable ssDNA) which remained in circulation was rapidly cleaved to 20,000-30,000 mol wt fragments by endonucleases, at least some of which could be demonstrated in plasma in vitro. Mononucleotide breakdown products appeared rapidly in circulation with no lag phase, suggesting that exonuclease activity was not dependent upon prior phagocytosis. Since no exonuclease activity could be demonstrated in plasma in vitro, it was postulated that breakdown of ssDNA by exonucleases occurs on the surface of hepatocytes of Kupffer cells.