BACKGROUND: Translational research is increasingly important as academic health centers transform themselves to meet new requirements of National Institutes of Health funding. Most attention has focused on T1 translation studies (bench to bedside) with considerable uncertainty about how to enhance T2 (effectiveness trials) and especially T3 (implementation studies). OBJECTIVE: To describe an innovative example of a T3 study, conducted as partnership research with the leaders of a major natural experiment in Minnesota to improve the primary care of depression. METHODS: All health plans in the state have agreed on a new payment model to support clinics that implement the well-evidenced collaborative care model for depression in the Depression Improvement Across Minnesota: Offering a New Direction initiative. The Depression Improvement Across Minnesota: Offering a New Direction study was developed in an ongoing partnership with the Initiative leaders from 7 health plans, 85 clinics, and a regional quality improvement collaborative to evaluate the implementation and its impacts on patients and other stakeholders. We agreed on a staggered implementation, multiple baseline research design, using the concepts of practical clinical trials and engaged scholarship and have collaborated on all aspects of conducting the study, including joint identification of patient and clinic survey recipients. RESULTS: Complex study methods have worked well through 20 months because of the commitment of all stakeholders to both the Initiative and the Study. Over 1500 subjects have been recruited from health plan information delivered weekly, and 99.7% of 316 physicians and administrators from all participating clinical organizations have completed the Study surveys. CONCLUSIONS: Partnership research can greatly facilitate translational research studies.