Background: Comparative effectiveness research (CER) documents important differences in antidepressants in terms of efficacy, safety, cost, and burden to the patient. Decision aids can adapt this evidence to help patients participate in making informed choices. In turn, antidepressant therapy will more likely reflect patients' values and context, leading to improved adherence and mood outcomes. Methods/Design: The objective of this study is to develop the Depression Medication Choice decision aid for use during primary care encounters, and to test its efficacy by conducting a clustered practical randomized trial comparing the decision aid to usual depression care in primary care practices. We will use a novel practice-based, patient-centered approach based on participatory action research that involves a multidisciplinary team of designers, investigators, clinicians, patient representatives, and other stakeholders for the development of the decision aid. We will then conduct a clustered practical randomized trial enrolling clinicians and their patients (n = 300) with moderate to severe depression from rural, suburban and inner city primary care practices (n = 10). The intervention will consist of the use of the depression medication choice decision aid during the clinical encounter. This trial will generate preliminary evidence of the relative impact of the decision aid on patient involvement in decision making, decision making quality, patient knowledge, and 6-month measures of medication adherence and mental health compared to usual depression care. Discussion: Upon completion of the proposed research, we will have developed and evaluated the efficacy of the decision aid depression medication choice as a novel translational tool for CER in depression treatment, engaged patients with depression in their care, and refined the process by which we conduct practice-based trials with limited research footprint.