To evaluate the predictive power of changes in levels of antibodies to double‐stranded DNA (anti‐dsDNA) as a predictor of disease exacerbations in systemic lupus erythematosus (SLE), we performed a prospective study on 72 unselected patients with SLE (mean duration of study 18.5 months, range 6–35 months). Patients were seen at least once every 3 months, and disease activity was scored according to a specific protocol. Plasma samples were obtained at least once every month and were assessed for anti‐dsDNA antibody (by the Crithidia luciliae assay, an enzymelinked immunosorbent assay [ELISA], and the Farr assay) and for complement components C3 and C4. Twenty‐seven of 33 disease exacerbations observed during the study period were accompanied by a positive test result for anti‐dsDNA antibody (27 by the Farr assay, 19 by the C luciliae assay, and 23 by the ELISA). Twenty‐four of these exacerbations were preceded by a significant increase in anti‐dsDNA antibody levels (23 by the Farr assay, 12 by the C luciliae assay, and 17 by the ELISA). The first observance of a significant increase in anti‐dsDNA antibody levels preceded the exacerbation by 8–10 weeks. Significant increases in anti‐dsDNA antibody levels not followed by an exacerbation were observed in 5 cases by the Farr assay, in 7 cases by the C luciliae assay, and in 3 cases by the ELISA; however, in 3 cases, 2 cases, and 1 case, respectively, these increases were followed by an increase in disease activity that did not fulfill the criteria for an exacerbation. Serial measurement of anti‐dsDNA antibody levels was more sensitive for predicting exacerbations than was measurement of C3 and/or C4 levels (P < 0.03). Serial assessment of anti‐dsDNA antibody levels, especially by the Farr assay, is a sensitive and reasonably specific method for predicting disease exacerbations in SLE.