We have earlier described a chronic relapsing experimental autoimmune encephalomyelitis (EAE) in B10.RIII mice induced with a peptide of myelin basic protein (MBP), mimicking the course of multiple sclerosis in man. We now show that estrogens ameliorate chronic EAE. Castration of female mice led to an earlier disease onset (day 9 +/- 2 postimmunization (p.i.) in castrated mice vs. day 16 +/- 4 p.i. in normal mice). Long-term treatment with high levels of 17 beta-estradiol (E2) given as Silastic implants led to a dramatically delayed onset of disease in both castrated and normal female mice (mean onset day was day 39 +/- 14 and day 50 +/- 3, respectively). Treatment of castrated females by injections of E2, at a concentration which induces the serum levels seen at late stage pregnancy, delayed the onset approximately 1 week (mean onset 21 +/- 8). In contrast, treatment with estriol (E3), which was also given at doses corresponding to those levels seen during pregnancy, delayed the disease onset for a longer time (mean onset day 31 +/- 5). Five times higher doses of E2, compared with those seen during pregnancy, were required to obtain similar effects as the low E3 dose. The same mouse strain (B10.RIII) is also susceptible to induction of collagen-induced arthritis (CIA). We show here that also CIA is suppressed by the same treatments with E2 and E3, suggesting that similar estrogen-mediated mechanisms may operate to suppress these T-cell-dependent autoimmune disease models.