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Successfully incorporating social determinants of health (SDH) screening into clinic workflows can help care teams provide targeted care, appropriate referrals, and other interventions to address patients' social risk factors. However, integrating SDH screening into clinical routines is known to be challenging. To achieve widespread adoption of SDH screening, we need to better understand the factors that can facilitate or hinder implementation of effective, sustainable SDH processes. The authors interviewed 43 health care staff and professionals at 8 safety net community health center (CHC) organizations in 5 states across the United States; these CHCs had adopted electronic health record (EHR)-based SDH screening without any external implementation support. Interviewees included staff in administrative, quality improvement, informatics, front desk, and clinical roles (providers, nurses, behavioral health staff), and community health workers. Interviews focused on how each organization integrated EHR-based SDH screening into clinic workflows, and factors that affected adoption of this practice change. Factors that facilitated effective integration of EHR-based SDH screening were: (1) external incentives and motivators that prompted introduction of this screening (eg, grant requirements, encouragement from professional associations); (2) presence of an SDH screening advocate; and (3) maintaining flexibility with regard to workflow approaches to optimally align them with clinic needs, interests, and resources. Results suggest that it is possible to purposefully create an environment conducive to successfully implementing EHR-based SDH screening. Approaching the task of implementing SDH screening into clinic workflows as understanding the interplay of context-dependent factors, rather than following a step-by-step process, may be critical to success in primary care settings.