Using the immunofluorescent (IF) assay with Crithidia luciliae smears, anti-native (n) DNA antibodies were detected in the sera of 12 of 20 systemic lupus erythematosus (SLE) patients, in 1 of 6 mixed connective tissue disease cases, in 2 of 38 patients with systemic sclerosis but in none of the sera from 96 normal subjects. All anti-nDNA antibodies were associated with antinuclear antibodies (ANA). However, occasionally sera were encountered in routine screening which appear to be positive for anti-DNA antibodies but negative for ANA. Studies of such sera indicate that this is a nonspecific reaction which can be abolished by treating sera with dextran sulfate or heparin. Treatment of SLE sera with these agents had no effect on their anti-nDNA antibody activity. Absorption of sera with Aerosil eliminated the false positive reactions with C. luciliae; however, this treatment also removed immunoglobulins, ANA and anti-nDNA antibodies. Evidence is reviewed which points to a role of complexes of low density lipoprotein and IgG in the nonspecific binding reactions with C. luciliae which is seen as false positive reactions for anti-nDNA antibodies.