Objective: To test the hypothesis that use of a clinical decision support (CDS) system in a primary care setting can reduce cardiovascular (CV) risk in patients. Materials and Methods: Twenty primary care clinics were randomly assigned to usual care (UC) or CDS. For CDS clinic patients identified algorithmically with high CV risk, rooming staff were prompted by the electronic health record (EHR) to print CDS that identified evidence-based treatment options for lipid, blood pressure, weight, tobacco, or aspirin management and prioritized them based on potential benefit to the patient. The intention-to-treat analysis included 7914 adults who met high CV risk criteria at an index clinic visit and had at least one post-index visit, accounted for clustering, and assessed impact on predicted annual rate of change in 10-year CV risk over a 14-month period. Results: The CDS was printed at 75% of targeted visits, and providers reported 85% to 98% satisfaction with various aspects of the intervention. Predicted annual rate of change in absolute 10-year CV risk was significantly better in CDS clinics than in UC clinics (-0.59% vs. +1.66%, -2.24%; P < .001), with difference in 10-year CV risk at 12 months post-index favoring the CDS group (UC 24.4%, CDS 22.5%, P < .03). Discussion: Deploying to both patients and providers within primary care visit workflow and limiting CDS display and print burden to two mouse clicks by rooming staff contributed to high CDS use rates and high provider satisfaction. Conclusion: This EHR-integrated, web-based outpatient CDS system significantly improved 10-year CV risk trajectory in targeted adults.