Postpartum depression effects 10% to 20% of women who give birth worldwide, and approximately 40% to 80% of cases are considered moderate to severe. The burden of this disorder is multifactorial, with financial, social, and health-related consequences for mothers and families. Conventional treatment of postpartum depression using antidepressants has been associated with improvements in the quality of mother-infant interaction and infant play. Treatment for postpartum depression using selective serotonin reuptake inhibitors often fails to achieve complete remission of symptoms, and the preventative effect of this medication remains unclear. A phase 2 study by this group found that brexanolone injections (a soluble, proprietary, β-cyclodextrin-based, intravenous formulation of allopregnanolone) had a robust antidepressant effect. This report shows the results of two phase 3, double-blind, randomized, placebo-controlled trials of brexanolone injection therapy to treat women with moderate to severe postpartum depression. The 2 phase 3 studies were carried out across 30 clinical research facilities and specialized psychiatric units in the United States. Studies 1 and 2 were carried out under an umbrella protocol that integrated outcome data with the previous phase 2 study. Subjects were enrolled for study 1 between August 1, 2016, and October 19, 2017, and for study 2 between July 25, 2016, and October 11, 2017. The trials included physically healthy females aged 18 to 45 years, 6 months postpartum or less at screening, with postpartum depression defined as 17-item Hamilton Rating Scale for Depression (HAM-D) score greater than 26 for study 1 and 20 to 25 for study 2. Patients determined to be eligible were randomly assigned (1:1:1 ratio) to receive brexanolone injection 90 μg/kg per hour (BRX90), brexanolone injection 60 μg/kg per hour (BRX60), or matching placebo infusion in study 1, or (1:1 ratio) BRX90 or matching placebo infusion in study 2. Infusions were administered over 60 hours, with an additional 12 hours for completion of study assessments. Patients were followed up until day 30. The primary outcome recorded for both studies was the mean change from baseline in HAM-D total score at 60 hours postinfusion. A total of 138 women were enrolled into study 1 (BRX90 n = 45, BRX60 n = 47, placebo n = 46) and 108 enrolled into study 2 (BRX90 n = 54, placebo n = 54). Demographics, baseline characteristics, and onset of postpartum depression were similar across all groups. After infusion in study 1, results showed a statistically significant least-squares mean reduction in HAM-D total score in the BRX60 group (19.5 points [SE 1.2]; −5.5; 95% confidence interval [CI], −8.8 to −2.2; P = 0.0013) and in the BRX90 group (17.7 points [1.2]; −3.7; 95%CI, −6.9 to −0.5; P = 0.0252) compared with the placebo group (14.0 points Health, Inc. All rights reserved. 220 Obstetrical and Gynecological Survey [1.2]). After infusion in study 2, results showed a statistically significant decrease in HAM-D total score in the BRX90 group (14.6 points [0.8]) compared with the placebo group (12.0 points [0.8]; −2.5%; 95% CI, −4.5 to 0.5; P = 0.0160). The results of this study show a robust decrease from baseline in least-squares mean HAM-D total scores after BRX90 and BRX60 infusions, regardless of initial HAM-D total score stratification. These findings are in agreement with results of the phase 2 trial and provide strong evidence for the efficacy and safety of brenaxolone injections in women with moderate to severe postpartum depression.