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Women experiencing severe perinatal mental illness during pregnancy or postpartum have unique needs when psychiatric hospitalization is indicated. Although many countries have established mother-baby psychiatric units, similar facilities have not been available in the US. In 2011, the University of North Carolina at Chapel Hill inaugurated the first Perinatal Psychiatry Inpatient Unit in the US. We describe the unique characteristics of the patient population and report clinical outcomes guiding development and refinement of treatment protocols. Ninety-two perinatal patients were admitted between September 2011 and September 2012, and 91 completed self-report measures at admission and discharge. Perinatal unipolar mood disorder was the most frequent primary diagnosis (60.43 %), and 11 patients (12 %) were admitted with psychosis. The data document clinically and statistically significant improvements in symptoms of depression, anxiety, and active suicidal ideation between admission and discharge (p < 0.0001), as assessed by the Edinburgh Postnatal Depression Scale, Patient Health Questionnaire, and Generalized Anxiety Disorder Scale. Overall functioning was also improved, demonstrated by a significant mean difference of -10.96 in total scores of the Work and Social Adjustment Scale (p < 0.0001). Data suggest that delivering specialized and targeted interventions for severe maternal mental illness in a safe and supportive setting produces positive patient outcomes.