Abstract Although childhood cancer is the leading cause of death by disease past infancy in the US, with 17,000 children younger than 21 years being diagnosed annually, survival has improved dramatically, and is now greater than 80% overall. Because of unequal access to services and adverse Social Determinants of Health (SDOH) affecting underserved populations, disparities in survival exist among minoritized youth with cancer. For example, Hispanic children have higher incidence of certain cancers and poorer survival rates than non-Hispanic White children. Minorities are severely under-represented in research. This means that cancer outcomes data are largely based on data from non-Hispanic White participants, and there is incomplete information to adequately assess treatment benefits for minorities. We showed that 53% of Latino parents declined research participation, compared to 20% of non-Hispanic White parents, in our institution. There are several barriers to informed consent for clinical trials. First, there are no mandates to ensure comprehension, and informed consent forms are complex, long, and difficult to understand. This leaves parents of children with cancer with an incomplete understanding of risks, procedures, randomization, alternative treatments, and the voluntary nature of clinical trial participation. Furthermore, pediatric cancer often requires urgent treatment, leaving little time for decision-making. We developed COMPRENDO (ChildhOod Malignancy Peer REsearch NavigatiOn), a peer-navigation intervention to improve research literacy and diversity in pediatric cancer clinical trials. In this intervention, trained peer-navigators, who have the lived experience of having a child diagnosed with cancer, provide in-hospital support. The goals of COMPRENDO are to improve parents’ informed consent experience and comprehension of informed consent for cancer treatment, to explain to parents terms to be discussed by the oncologist during the treatment conference, to introduce to parents concepts of clinical trials and research, and to facilitate and empower shared decision-making. In a pilot study at Rady Children’s Hospital-San Diego, this intervention showed a significant increase in comprehension of therapeutic trials, particularly in Hispanic and Spanish-speaking parents. The demographics of children with cancer enrolled in clinical trials should be comparable to the US population, and approaches to improve enrollment must also be tailored to specific settings. Structural barriers for participation of minorities should be considered during study and informed consent design and planning. Strategies to increase clinical trial enrollment of minority individuals include: Provider-level training on patient-provider communication, development of linguistically appropriate tools, and promotion of culturally aware staff. Key strategies at the patient-level include building trust; education and awareness of clinical trials; implementation of culture, language, and health literacy-concordant interventions; and initiatives to address adverse SDOH. Citation Format: Paula Aristizabal. Increasing Diversity in Pediatric Cancer Clinical Trials: Challenges and Opportunities [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr IA013.