© 2020 Wiley Periodicals LLC Objective: Due to the absence of a licenced vaccine or drug for treatment of Ebola patients during the 2014–2016 West Africa outbreak, frontline nurses were at increased risk of exposure. Hence, they were prioritized to participate in clinical trials to receive experimental therapeutics. To our knowledge no study has explored the nurses' experiences of their decision-making process when volunteering in clinical trials using unproven agents, which is the purpose of this qualitative study. Methods: This study, part of a larger Ebola study, thematically analyzed the interview data of nine nurses recruited from Sierra Leone, Guinea and Liberia; of which four joined a convalescent plasma trial and five a vaccine trial. Results: In their decision-making process to partake in a clinical trial, nurses identified two distinct decision points: the initial commitment followed by the point of no return when they presented themselves to participate. Each of these decisions were influenced by risk versus benefits calculations, and contextual factors. Conclusion: Results showed the need for more health education and communication around the unproven agents in order for nurses to make informed decisions.