INTRODUCTION: Pregnant and postpartum women (PPW) in sub-Saharan Africa are at disproportionately high risk of HIV infection compared to non-pregnant women. When used consistently, pre-exposure prophylaxis (PrEP) can prevent HIV acquisition and transmission to the foetus or infant during these critical periods. Recent studies have demonstrated associations between mental health challenges (e.g. depression and traumatic stress associated with intimate partner violence) and decreased PrEP adherence and persistence, particularly among adolescents, younger women and women in the postpartum period. However, mental health is not currently a major focus of PrEP implementation research and programme planning for PPW. DISCUSSION: PrEP implementation programmes for PPW need to assess and address mental health barriers to consistent PrEP use to ensure effectiveness and sustainability in routine care. We highlight three key research priorities that will support PrEP adherence and persistence: (1) include mental health screening tools in PrEP implementation research with PPW, both to assess the feasibility of integrating these tools into routine antenatal and postpartum care and to ensure that limited resources are directed towards women whose symptoms may interfere most with PrEP use; (2) identify cross-cutting, transdiagnostic psychological mechanisms that affect consistent PrEP use during these periods and can realistically be targeted with intervention in resource-limited settings; and (3) develop/adapt and test interventions that target those underlying mechanisms, leveraging strategies from existing interventions that have successfully mitigated mental health barriers to antiretroviral therapy use among people with HIV. CONCLUSIONS: For PPW, implementation of PrEP should be guided by a robust understanding of the unique psychological difficulties that may act as barriers to uptake, adherence and persistence (i.e. sustained adherence over time). We strongly encourage PrEP implementation research in PPW to incorporate validated mental health screening tools and ultimately treatment in routine antenatal and postnatal care, and we stress the potential public health benefits of identifying women who face mental health barriers to PrEP use.