Postpartum psychosis, the most serious postpartum psychiatric condition, is often resistant to psychopharmacotherapy, and relatively considerable number of women (4% in one series) may commit infanticide. Because estrogen reportedly is an effective therapy for postnatal depression and may prevent affective disorder, estrogen therapy was evaluated in 10 consecutive women admitted with puerperal psychosis. Psychiatric symptoms had developed in the patients, whose age averaged 31 years, approximately 12 days after delivery, and the women had had symptoms for an average of 10 weeks at the time they entered the study. Six of the women had received psychotherapy or neuroleptic medication but did not respond adequately. Serum estradiol was measured at weekly intervals during 6 weeks of treatment with sublingual 17&bgr;-estradiol. The dose was 1 mg three to six times per day, and the goal was a serum level of 400 pmol/liter (about one-third of the menstrual peak). After the first week, the average daily dose was 4.7 mg. Neuroleptic drugs were gradually withdrawn, and efficacy was measured using the Brief Psychiatric Rating Scale (BPRS).Baseline serum estradiol levels in all patients were below 110 pmol/liter, the threshold value for gonadal failure. During treatment the levels rose gradually to reach an average of 692 pmol/liter at week 6. None of the women menstruated during 6 weeks of follow-up. Florid psychotic symptoms were invariably present at the outset, when the average total BPRS score was 78. Symptom scores decreased significantly to 19 within 1 week, and within 2 weeks the women were nearly free of psychiatric symptoms. The total BPRS score averaged 4 at this time. Serum estradiol levels increased as the symptoms resolved. A women who stopped taking estradiol experienced an abrupt drop in serum estradiol and once again exhibited severe symptoms. The findings in this small pilot study suggest that an insufficient level of estradiol plays a role in the development of postpartum psychosis and that estradiol therapy may be a rational treatment.