Serial serum samples from NZB/NZW F1 mice were studied by sucrose density gradient ultracentrifugation and filter radioimmunoassay for the immunoglobulin class of antibodies to double-stranded DNA and single-stranded RNA (Poly A). These antibodies occur spontaneously during the course of an autoimmune disease resembling systemic lupus erythematosus. Study of serum samples at 2-week intervals showed the sequential appearance of 19S followed by 7S anti-nucleic acid antibodies, an earlier commitment to 7S antibodies in female compared to male mice, and an independent and unrelated switching mechanism (19S-7S) for antibodies to DNA and Poly A. The more severe disease in female mice is correlated with an earlier appearance of 7S anti-DNA antibodies. This sequential and ordered appearance of antibodies to nucleic acids is discussed in relation to possible immunologic regulatory mechanisms.