Abstract A study was undertaken to assess postpartum psychological distress and to evaluate a novel approach to treatment. Kellner's Symptom Questionnaire proved to be a valuable predictive tool for anxiety, depression, somatic symptoms, and hostility in 190 women during puerperium. This epidemiologic investigation was followed by a two-phase comparative clinical study. The first phase was a double-blind trial of oral S-adenosylmethionine (SAMe) 1600 mg/day versus placebo for 30 days administered to two groups of 30 patients each. Compared with the patients receiving placebo, patients receiving SAMe exhibited improved symptom questionnaire total scores and depression and anxiety scores by day 10 of treatment. Progressive improvement was observed throughout the duration of the study. The second phase of the study was an open trial comparing 40 SAMe-treated patients with the epidemiologic group of patients as controls. After 30 days of treatment, the patients receiving SAMe showed a significant improvement in both total scores and depression and anxiety items compared with the control group. We conclude that SAMe is an effective treatment for reducing or relieving the signs and symptoms of psychological distress during puerperium.