High utilizers of nonpsychiatric health care services have disproportionally high rates of undiagnosed or undertreated depression. To determine the impact of offering a systematic primary care-based depression treatment program to depressed "high utilizers" not in active treatment. Randomized clinical trial. One hundred sixty-three primary care practices in 3 health maintenance organizations located in different geographic regions of the United States. A group of 1465 health maintenance organization members were identified as depressed high utilizers using a 2-stage telephone screening process. Eligibility criteria were met by 410 patients and 407 agreed to enroll: 218 in the depression management program (DMP) practices and 189 in the usual care (UC) group. The DMP included patient education materials, physician education programs, telephone-based treatment coordination, and antidepressant pharmacotherapy initiated and managed by patients' primary care physicians. Depression severity was measured using the Hamilton Depression Rating Scale (Ham-D) and functional status using the Medical Outcomes Study 20-item short form (SF-20) subscales. Outpatient visit and hospitalization rates were measured using the health plan's encounter data. Based on an intent-to-treat analysis, at least 3 antidepressant prescriptions were filled in the first 6 months by 151 (69.3%) of 218 of DMP patients vs 35 (18.5%) of 189 in UC (P < .001). Improvements in Ham-D scores were significantly greater in the intervention group at 6 weeks (P = .04), 3 months (P = .02), 6 months (P < .001), and 12 months (P < .001). At 12 months, DMP intervention patients were more improved than UC patients on the mental health, social functioning, and general health perceptions scales of the SF-20 (P < .05 for all). In depressed high utilizers not already in active treatment, a systematic primary care-based treatment program can substantially increase adequate antidepressant treatment, decrease depression severity, and improve general health status compared with usual care.