Dietary modulation has the potential to prevent or ameliorate systemic lupus erythematosus (SLE). Indole-3-carbinol (I3C), which is abundant in cruciferous vegetables, was evaluated in a murine model of SLE because of its antiestrogenic activities. Female (NZB x NZW) F1 mice, which develop SLE, were fed an AIN76A diet without or with 0.2 g/kg I3C, starting soon after weaning or at 5 mo of age. At 12 mo of age, 80% of mice fed the I3C-supplemented diet soon after weaning were alive compared with only 10% of controls. When experimental diets were initiated at 5 mo of age, 100% of I3C fed mice and 30% of controls were alive at 12 mo of age. Anti-double-stranded DNA (dsDNA) antibodies developed in all groups, although at several time points, the levels produced in I3C-fed mice were significantly lower. Renal disease (proteinuria, histologic changes, IgG immune complex deposition, subepithelial deposits and diffuse epithelial cell foot process effacement) was more severe in controls with both protocols. The estrogen urinary metabolite ratio of 2- to 16alpha-hydroxyestrone was increased in I3C-fed mice. These findings demonstrate a profound effect of dietary I3C in experimental SLE.