To evaluate the properties of antibodies to bacterial DNA in the sera of normal human subjects (NHS) and patients with systemic lupus erythematosus (SLE), the effects of ionic strength and pH on their binding to single-stranded DNA (ssDNA) from Micrococcus lysodeikticus (MC) were measured. By ELISA, antibodies to MC ssDNA in NHS showed greater activity at high ionic strength (0.2-1.0 M) than antibodies in lupus sera. Similarly, antibodies in NHS had higher activity at pH 9 than lupus anti-DNA. Competition binding assays indicated, moreover, that NHS anti-DNA showed greater inhibition by DNA than lupus anti-DNA at comparable inhibitor concentrations. Together, these results suggest that antibodies to MC ssDNA in NHS and SLE sera may differ in their mode of interaction with bacterial DNA and that NHS can generate high avidity antibodies to at least certain DNA determinants.