5 Background: Implementation of guideline-recommended distress screening in oncology remains challenging. Evidence suggests that multicomponent care pathways to identify distress severity with algorithm-based referral and management are effective, yet testing of pragmatic implementation in community settings remains limited. We conducted a pragmatic randomized trial of a distress screening program in a large healthcare system to evaluate effectiveness and simultaneously examined implementation outcomes. Methods: We designed a highly pragmatic study per the Pragmatic-Explanatory Continuum Indicator Summary-2 with adaptive workflow design. Randomization was at the medical center level (N=6); eligible patients had a new diagnosis of breast cancer (no exclusions). Eligible patients were offered the distress screening program as part of usual care: PHQ-9 screening, algorithm-based scoring and referral, referral tracking, and audit and feedback of performance data. Control sites had access to the PHQ-9 and scoring algorithm. We compared number screened, distress severity, and referral. We conducted qualitative interviews with stakeholders on implementation barriers and facilitators. Results: We enrolled 1,436 eligible patients; 692 control, 744 intervention. Groups were similar in demographic and tumor characteristics (Table); 80% of patients completed screening at intervention sites vs <1% at control sites. Of those screened at intervention sites, 10% scored in the medium/high range indicating need for referral; 94% received an appropriate referral. We conducted 20 interviews; the program was found to be highly feasible and acceptable. Conclusions: Our pragmatic, adaptive approach resulted in the large majority of patients screened and appropriately referred with a high degree of acceptability and feasibility. Our results can promote more widespread, sustained adoption of effective distress screening programs. Clinical trial information: NCT02941614. [Table: see text]