Background: Many patients with chronic disease do not reach goals for management of their conditions. Self-management support provided by medical assistant health coaches within the clinical setting may help to improve clinical outcomes, but most studies to date lack statistical power or methodological rigor. Barriers to large scale implementation of the medical assistant coach model include lack of clinician buy-in and the absence of a business model that will make medical assistant health coaching sustainable. This study will add to the evidence base by determining the effectiveness of health coaching by medical assistants on clinical outcomes and patient self-management, by assessing the impact of health coaching on the clinician experience, and by examining the costs and potential savings of health coaching. Methods/Design. This randomized controlled trial will evaluate the effectiveness of clinic-based medical assistant health coaches to improve clinical outcomes and self-management skills among low-income patients with uncontrolled type 2 diabetes, hypertension, or hyperlipidemia. A total of 441 patients from two San Francisco primary care clinics have been enrolled and randomized to receive a health coach (n = 224) or usual care (n = 217). Patients participating in the health coaching group will receive coaching for 12 months from medical assistants trained as health coaches. The primary outcome is a change in hemoglobin A1c, systolic blood pressure, or LDL cholesterol among patients with uncontrolled diabetes, hypertension and hyperlipidemia, respectively. Self-management behaviors, perceptions of the health care team and clinician, BMI, and chronic disease self-efficacy will be measured at baseline and after 12 months. Clinician experience is being assessed through surveys and qualitative interviews. Cost and utilization data will be analyzed through cost-predictive models. Discussion. Medical assistants are an untapped resource to provide self-management support for patients with uncontrolled chronic disease. Having successfully completed recruitment, this study is uniquely poised to assess the effectiveness of the medical assistant health coaching model, to describe barriers and facilitators to implementation, and to develop a business case for sustainability. Trial registration. ClinicalTrials.gov identifier NCT-01220336. © 2013 Willard-Grace et al.; licensee BioMed Central Ltd.