Steroid hormones, which affect development of reproductive traits, alter immune responses in rodents and appear to control severity of disease in F1 hybrid NZB/W mice, an animal model of systemic lupus erythematosus. We tested the hypothesis that exposure of NZB/W fetuses to altered hormonal environments would influence subsequent expression of autoimmune renal disease and affect longevity. NZB females, pregnant with NZB/W fetuses, were treated from Days 13-18 of gestation with testosterone or the antiandrogen, flutamide. Similar treatments were carried out in C57BL/6 dams mated to DBA/2 males to permit comparison with nonautoimmune hybrid mice. Serum concentrations of testosterone were greater in testosterone-implanted dams of both strains, but concentrations of estradiol were greater only in C57BL/6 dams treated with flutamide. Alpha fetoprotein (AFP), which binds estrogen and modulates immune responsiveness, was greater in serum from both groups of testosterone-treated dams, while flutamide treatment increased serum AFP only in NZB dams. We conclude that factors governing circulating estradiol and AFP differed in pregnant NZB and C57BL/6 females. Morphological analyses confirmed effects of hormonal manipulation on the developing fetuses. Testosterone implants resulted in female offspring with greater anogenital spaces, and treatment of dams with flutamide eliminated the expected difference between anogenital spaces in females and males. Effects of altered prenatal hormonal environments on immune-mediated disease in NZB/W offspring were examined in a longevity study. Early deaths were delayed in NZB/W females produced by flutamide-treated dams. An unexpected result was observed in NZB/W males. Male offspring from both testosterone- and flutamide-treated mothers lived longer than males from control dams. This paradox suggested that a characteristic shared by both groups of treated NZB dams had similar effects on the developing fetuses. It is proposed that elevated concentrations of AFP modulated the course of autoimmune disease and contributed to increased longevity in NZB/W offspring of treated dams.