Background: Little progress has been made in the past decade on improving clinical trial enrollment in the United States, particularly for adults and those in ethnic and racial minorities. Oncology nurses play a pivotal role in identifying and addressing patient concerns about clinical trials. Objectives: The aim was to identify patient-related barriers to clinical trial participation using a mixed-method patient survey and offer insights to develop evidence-based implementation strategies to address these barriers. Methods: A retrospective survey was conducted of patients who were not interested in participating in a clinical trial to quantify the reasons these patients chose not to participate. Directed qualitative content analysis was used to identify themes that emerged from the write-in responses. Findings: The greatest patient-reported barriers were misperceptions about placebos, not wanting to feel like a ‘human guinea pig’, uncertainty surrounding clinical trial treatment effectiveness compared to standard care, and concerns about additional appointments or tests. Oncology nurses can address patient enrollment barriers by providing targeted education and participating in the informed consent process.