Abstract Purpose: Tumor genomic testing and cancer clinical trial enrollment provide key access to precision cancer therapeutics and supportive care options to enhance the patient experience. However, physician and patient barriers limit participation of patients who are historically underrepresented in genomic studies and clinical trials [historically underrepresented patients (HUP)], thereby decreasing generalizability for those most negatively affected by cancer diagnosis. We interviewed patients to identify factors impacting genomic testing uptake and clinical trial enrollment. Methods: From 09/2021 - 12/2021 we interviewed 16 patients diagnosed with cancer seen at an ambulatory oncology center. Patients were HUP (Black, American Indian or Alaska Native, Native Hawaiian or other Pacific Islander, Hispanic/Latinx, or older adult [70 years or older], or from a low-income zip code). From non-inclusive groups, patients identified as: 3 primarily spoke a language other than English, 9 Black, 3 other race, 6 Hispanic, and 3 aged 70 years or older. One-on-one interviews utilized a structured interview guide and lasted approximately 45 minutes. Participants were recruited until thematic saturation was reached then transcripts coded for major patterns and themes. Results: Regarding tumor genomic testing, many patients were unsure if they received testing or if testing was recommended (citing possible confusion with medical terminology or overwhelm with information). Cited barriers included education (not understanding the benefit of participating, investigational drug/device identity, the procedures and processes involved), mistrust of research (specifically concerns over data privacy); and logistical accessibility (cost, time away from work, transportation). Those tested found it to be an easy process. Several cited that a patient advocate or social worker would be beneficial to navigate the process. Barriers around clinical trial enrollment included education (the risks of participating/side effects, size of the study, investigational drug/device identity), mistrust of research (data privacy, inclusion of HUP in trial, loss of autonomy in decision making), and logistical accessibility (time commitment). HUP who participated in a clinical trial appreciated the additional psychosocial support and clinical monitoring. Patients were emphatically interested in participating in genomic testing and cancer clinical trials when presented as the best course of care, though concerns about side effects from clinical trials persisted. Conclusion: Patient barriers to tumor genomic testing and cancer clinical trials center around education, mistrust in research, and logistical accessibility. Patients who participated in genomic testing and clinical trials did have a positive experience. Barriers may be addressed with personalized education and coaching, including supportive resources referral. Citation Format: Ellana K. Haakenstad, Jane Roberts, Anna C. Revette, Wendy Loeser, Joseph Grider, Andrea Kruse, Alissa Gentile, Rachel Freedman, Neal I. Lindeman, Olga Kozyreva, Pedro Sanz-Altamira, Christopher S. Lathan, Michael Hassett, Ethan Cerami, Annette S. Kim, Danielle K. Manning, Jonathan Nowak, Marios Giannakis, R Coleman Lindsley, William C. Hahn, Barrett J. Rollins, Levi Garraway, Bruce E. Johnson, Nadine Jackson McCleary. Persistent patient barriers to genomic testing in ambulatory oncology. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5524.