OBJECTIVES: Antidepressants are the first line treatment for moderate to severe major depressive disorder (MDD) in perinatal and general populations. However, there appears to be paucity of evidence around antidepressant use in women with postpartum depression or anxiety. Selection of an appropriate antidepressant is crucial in promoting efficacy, optimizing tolerability, and managing comorbid anxiety or depression. Our aim was to investigate the treatment effect and tolerability profile of desvenlafaxine, and to examine the functionality of women with postpartum depression or anxiety after desvenlafaxine treatment. METHODS: Fifteen postpartum women with depression or anxiety completed this 12-week prospective pilot study with a flexible dose of desvenlafaxine (50-100 mg). Participants were recruited at a tertiary care level program. Measures of depression (Montgomery-Åsberg Depression Rating Scale, MADRS), anxiety (Hamilton Anxiety Rating Scale, HAM-A), worry (Penn State Worry Questionnaire, PSWQ) and functional impairment (Sheehan Disability Scale, SDS) were completed at baseline, 8 weeks, and 12 weeks. RESULTS: In the intention-to-treat analysis (n = 17), the majority of women responded to medication (88.2%, n = 15), and reached remission of depressive (82.4%, n = 14) and anxiety symptoms (82.4%, n = 14). Remission of depression was achieved in a mean of 6.9 weeks [standard deviation (SD) = 3.01] at a mean dose of 71 mg/day (SD = 25.7). Significant decreases were observed on PSWQ worry scores (p < 0.0001) and SDS scores for social (p < 0.0001) and family life impairment (p < 0.0001). The medication was generally well tolerated. CONCLUSION: The results of our prospective pilot study suggest that treatment with desvenlafaxine of postpartum mothers with depression or anxiety can lead to symptom remission and restoration of functionality.