Various mammalian species contain an anionic serum protein that reacts specifically with native DNA. It is considerably less reactive with single-strand DNA and does not react with monodeoxyribonucleotides, homopolyribonucleotides, or duplexes of homopolyribonucleotides. Synthetic dA.dT was an effective inhibitor of the reaction with native DNA, while Micrococcus luteus DNA and dG.dC were not inhibitory. This protein was encountered in the course of studies on DNA antibodies. Although it reacted with red cells coated with DNA and gave agar precipitation bands, it was clearly distinct from DNA antibodies. It was found in the serum of all animals of a given species, migrated as an alpha-beta globulin, and did not crossreact with gammaglobulins. It reacted with DNA in solution to give precipitation curves that were strongly influenced by changes in ionic strength. The protein was isolated from canine serum by precipitation with DNA and purified to homogeneity, as judged by immunochemical and electrophoretic criteria.A similar protein was found in mink, equine, and other sera, but not in human sera. Previous studies on DNA antibodies in certain experimental animals may have given false positive results due to this protein.