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Women often seek antidepressant alternatives for major depressive disorder (MDD) in anticipation of or during pregnancy. In this preliminary study, EnBrace HR, a prenatal supplement containing methylfolate, was investigated for depressive relapse prevention and for acute treatment of MDD in women planning pregnancy or during pregnancy.This 12 week open label study included women with histories of MDD who were planning pregnancy or pregnant <28 weeks. At enrollment, Group 1 participants were well (not depressed) and planned to discontinue antidepressants for pregnancy. Group 2 participants were depressed. Primary outcome variables by group included MDD relapse and depressive symptoms, verified with the Mini International Neuropsychiatric Interview and the Montgomery Åsberg Depression Rating Scale (MADRS), respectively. Biomarkers of inflammation and the folate cycle were collected.Group 1 participants (N = 11) experienced lower rates of depressive relapse (27.3%; P = .005) than expected from a historical comparison group and no significant changes in MADRS scores. Group 2 participants (N = 6) experienced significant improvements in MADRS scores (P = .001), with 5 (83.3%) improving >50% and 1 improving 33.3%. One adverse event occurred, a hospitalization for depression.Results suggest EnBrace HR is a well tolerated intervention with potential efficacy for prevention and treatment of perinatal depression. Larger controlled trials are necessary.