<p>Sickle cell disease (SCD) is an inherited blood disorder that results in abnormal hemoglobin and crescent-shaped red blood cells. While SCD was discovered over a century ago, it has historically had fewer new drugs in development compared with other conditions, negatively impacting patients’ therapeutic options. Recently, there has been a substantial increase in the development of novel therapies for SCD, but the perception that people with SCD (PwSCD) are hesitant to participate in clinical trials remains pervasive. Enhancing our understanding of factors that influence the participation of PwSCD in clinical trials is critical to ensuring trial completion, thereby supporting the development of new treatments. The Learnings and Insights into Sickle Cell Trial Experiences (LISTEN) Survey was a global, mixed methods study where PwSCD and health care professionals (HCPs) were surveyed about the importance of specific factors such as impact on daily life, treatment impact, and wider clinical trial outcomes, as well as basic trial information and further considerations, when deciding to participate in a trial. PwSCD were surveyed about their personal perspectives whereas HCPs were surveyed about their perceptions of patient perspectives towards these factors and channels. In the United States, we identified areas of disconnect between the perspectives of PwSCD and HCPs. Additionally, geographic region, education, income, sex, disease severity, and trial experience contextualized PwSCD responses and provided additional insights. Results from this survey may guide the design of future clinical trials and strengthen how HCPs and trial sponsors communicate with PwSCD, thereby reducing trial participation barriers.</p>