Sex hormones affect (auto)immune responses in various ways. Investigations of the effects of estrogens have produced contradictory results. We studied the effects of gender, gonadectomy and of (supra)physiological doses of (the orally active) ethinylestradiol (EE) in two spontaneous autoimmune disease models: the NZB/NZW F1 and NOD mice. In both models we confirmed the female preponderance and the aggravating effects of gonadectomy in males but not in females. The accelerated mortality found in NZB/W mice treated with supraphysiological doses of EE was not associated with increased proteinuria, increased IgG-type anti-DNA levels or increased mononuclear cell infiltrations in the submandibular gland. In contrast, we found a severe reduction in body weight and in the weights of various organs (indications of toxicity), and a decrease rather than an increase in proteinuria and in mononuclear cell infiltrations (indications for autoimmunity). Physiological doses of EE did not significantly affect disease symptoms. In the NOD model a near-physiological, non-toxic dose of EE did not cause consistent changes on immunological disease symptoms either. Therefore, we conclude that the sexual dichotomy in spontaneous autoimmune models is due to protective effects of androgens and that the mortality by estrogens is due to toxic effects rather than accelerated autoimmunity.