OBJECTIVES: Because clinical outcomes of depression treatment in primary care settings tend to be poor, we developed and evaluated the efficacy of two augmentations to antidepressant treatment to be delivered by primary care nurses. METHODS: We conducted a randomized trial comparing usual care, telehealth care, and telehealth care plus peer support for depressed patients seen in primary care in an HMO setting. Assessments were conducted at baseline, six weeks and six months after study enrollment at two managed-care, adult primary-care clinics. Participants included 303 patients recently started on antidepressants. The intervention consisted of: telehealth care; emotional support and focused behavioral interventions in 10 seven-minute calls over four months by specially trained primary-care nurses and peer support; telephone and in-person supportive contacts by trained Health Plan members recovered from depression. Primary outcome measures were the Hamilton Rating Scale for Depression, Beck Depression Inventory, Mental and Physical Functioning (Short Form 12), and treatment satisfaction and medication adherence questionnaires. RESULTS: Nurse-based telehealth patients with or without peer support more often experienced 50% improvement on the Hamilton at six weeks (50% vs. 37%, P = .01) and six months (57% vs. 38%, P = .003), and on the Beck at six months (48% vs. 37%, P = .05). Greater quantitative reduction in symptom scores on the Hamilton at six months (10.4 vs. 8.1, P = .006) were observed. Telehealth care improved mental functioning at six weeks (47.1 vs. 42.6, P = .004) and treatment satisfaction at six weeks (4.41 vs. 4.17, P = .004) and six months (4.20 vs. 3.94, P = .001). Medication adherence was the same in all groups and adding peer support to telehealth care did not improve the main outcomes. CONCLUSION: Nurse Telehealth Care improves clinical outcomes of antidepressant treatment, improves patient satisfaction, and fits well in primary care. The nurse telehealth care program has been implemented in Maine, Ohio and Southern California.