IMPORTANCE For antidepressants, the translation of evidence of comparative effectiveness into practice is suboptimal. This deficit directly affects outcomes and quality of care for patients with depression. To overcome this problem, we developed the Depression Medication Choice (DMC) encounter decision aid, designed to help patients and clinicians consider the available antidepressants and the extent to which they improved depression and other issues important to patients. OBJECTIVE Estimate the effect of DMC on quality of the decisionmaking process and depression outcomes. DESIGN, SETTING, AND PARTICIPANTS We conducted a cluster randomized trial of adults with moderate to severe depression considering treatment with an antidepressant. Primary care practices in 10 rural, suburban, and urban primary care practices across Minnesota and Wisconsin were randomly allocated to treatment of depression with or without use of the DMC decision aid. INTERVENTION Depression Medication Choice, a series of cards, each highlighting the effect of the available options on an issue of importance to patients for use during face-to-face consultations. MAIN OUTCOMES AND MEASURES Decision-making quality as judged by patient knowledge and involvement in decision making, patient and clinician decisional comfort (Decisional Conflict Scale) and satisfaction, encounter duration, medication adherence, depression symptoms, and the Patient Health Questionnaire for depression (PHQ-9). RESULTS We enrolled 117 clinicians and 301 patients (67%women; mean [SD] age, 44  years; mean [SD] PHQ-9 score, 15 ) into the trial. Compared with usual care (UC), use of DMC significantly improved patients' decisional comfort (DMC, 80% vs UC, 75%; P = .02), knowledge (DMC, 65%vs UC, 56%; P = .03), satisfaction (risk ratio [RR], from 1.25 [P = .81] to RR, 2.4 [P = .002] depending on satisfaction domain), and involvement (DMC, 47%vs UC, 33%; P.001). It also improved clinicians' decisional comfort (DMC, 80% vs UC, 68%; P .001) and satisfaction (RR, 1.64; P = .02). There were no differences in encounter duration, medication adherence, or improvement of depression control between arms. CONCLUSIONS AND RELEVANCE The DMC decision aid helped primary care clinicians and patients with moderate to severe depression select antidepressants together, improving the decision-making process without extending the visit. On the other hand, DMC had no discernible effect on medication adherence or depression outcomes. By translating comparative effectiveness into patient-centered care, use of DMC improved the quality of primary care for patients with depression.