The F₁ hybrid of New Zealand black and New Zealand white mice—the NZB/NZW mouse—spontaneously develops a disease similar to human systemic lupus erythematous, characterized by impaired cell‐mediated and enhanced humoral immune responses, development of antibodies to nuclear antigens, and immune complex glomerulonephritis. Because there is experimental evidence that prostaglandin E₁ (PGE₁) can enhance T‐cell function and cell‐mediated responses and suppress B‐cell activity, NZB/NZW mice were treated with 200 μg PGE₁ subcutaneously once or twice daily from 6 weeks of age. PGE₁ treatment of female and male mice prevents glomerular deposition of immunoglobulins and complement (monitored by immunofluorescence), and development of the proliferative glomerulonephritis (determined by light and electron microscopy) characteristic of untreated NZB/NZW mice. After 1 year of treatment, 18 of 19 female mice survived, whereas only 2 of 19 untreated control mice were alive. Male mice treated with 200 μg PGE₁ daily were also protected: 9 of 11 versus 2 of 9 untreated mice were alive at 65 weeks. PGE₁ treatment did not prevent development of antibodies to nuclear material in any of the treated groups.