BackgroundKey populations (KPs) such as female sex workers (FSWs), men who have sex with men (MSM), people who inject drugs (PWID), and their partners contribute more than a quarter (27.5%) of new HIV infection in Ghana. Oral pre-exposure prophylaxis (PrEP) can substantially reduce HIV acquisition among this group. While the available research indicates KPs willingness to take PrEP in Ghana, little is known about the position of policymakers and healthcare providers on the introduction of PrEP for KPs.MethodsQualitative data were collected from September to October 2017 in the Greater Accra (GA) and Brong-Ahafo (BA) regions of Ghana. Key informant interviews were conducted with 20 regional and national policymakers and supplemented with In-depth Interviews with 23 healthcare providers to explore their level of support for PrEP and their perspectives on challenges and issues to consider for oral PrEP implementation in Ghana. Thematic content analysis was used to unearth the issues emerging from the interviews.ResultsPolicymakers and healthcare providers in both regions expressed strong support for introducing PrEP for KPs. Key concerns regarding oral PrEP introduction included potential for behavioral disinhibition, non-adherence and side effects of medication, cost and long-term financial implications, and stigma related to HIV and key populations. Participants stressed the need to integrate PrEP into existing services and the provision of PrEP should start with high risk groups like sero-discordant couples, FSWs and MSM.ConclusionsPolicymakers and providers recognize the value of PrEP in cubing new HIV infections but have concerns about disinhibition, non-adherence, and cost. Therefore, the Ghana health service should roll-out a range of strategies to address their concerns including: sensitization with providers to mitigate underlying stigma towards KPs, particularly MSM, integration of PrEP into existing services, and innovative strategies to improve continued use of PrEP.