To analyze mistrust in clinical research among racially and ethnically marginalized communities using Bronfenbrenner’s socioecological systems framework. The interconnected stratification of these systems serves as a magnifying lens to closely understand the mechanistic complexities that contribute to mistrust.

From November 2023 through May 2024, we conducted nine focus groups with community members (n = 51) and stakeholders (n = 50) in Dallas, Texas. Focus group narratives were analyzed deductively using Bronfenbrenner’s four levels of the socioecological systems and thematically analyzed within the scope of mistrust.

We identified twelve themes organized under the four socioecological systems. At the macrosystems level: (1) generational trauma and systemic mistrust, (2) the legacy of unethical research practices, (3) systemic racism and discrimination, and (4) institutional betrayal and sense of exploitation; at the exosystem level: (5) systemic barriers to access and (6) inequitable research practice; at the mesosystem level: (7) the legacy of systemic and cultural injustice, (8) decision making in the context of social inequality and (9) building and maintaining trust; and at the microsystem level:(10) building rapport, (11) honesty and transparency, and (12) negative past experiences and fear of harm.

Earning the confidence and trust of participants requires legitimizing a community’s narrative by explicitly acknowledging awareness of historical injustices and ongoing systemic inequities, maintaining integrity and ethical behavior, and building rapport.

Addressing mistrust to increase clinical trial participation, especially among those from historically underserved communities, is necessary to reduce disparities and ensure equitable healthcare for all populations.