<h2>Abstract</h2><h3>Background</h3> Clinical trials provide gold standard evidence for policy. Local investigator-initiated trials could generate highly relevant data for national governments of low-income and middle-income countries, but too few are done and information about how to facilitate them is scarce. We identified barriers and enablers to such trials in Ethiopia and Cameroon. <h3>Methods</h3> Our multisite, prospective qualitative study—done in Ethiopia and Cameroon—consisted of in-depth interviews (n=22), focus group discussions (n=9), and process mapping exercises (n=7). Local health-researchers with varying trial experience, senior stakeholders, and regulators were recruited through snowball sampling (n=72). Approval was obtained from home, local, and national review boards and verbal or written consent was obtained from participants. We assessed data by thematic analysis. <h3>Findings</h3> System and organisational barriers to trial conduct were similar between Ethiopia and Cameroon: low resources, weak regulatory and administrative systems, few learning opportunities, little human and material capacity, and few incentives for doing research. In Ethiopia, lack of awareness, confidence, and motivation to undertake trials were key individual barriers, but in Cameroon, environments that discourage personal initiative were more problematic. Learning opportunities and international collaboration were important enablers in both countries, but encouraging more active involvement of researchers at all stages of the trial process facilitated trial undertaking in Cameroon especially. <h3>Interpretation</h3> In addition to context-specific issues, we have shown the existence of perennial organisational and system barriers in Africa. These findings indicate a common need to make system-wide changes and build receptive research environments for researchers in low-income and low-to-middle-income countries. <h3>Funding</h3> The Global Health Network (Bill & Melinda Gates Foundation), Nuffield Department of Medicine Doctoral Prize Studentship.