This study was designed to investigate the impact of a time-phased patient education program (RHYTHMS) on medication compliance and treatment outcomes of primary care patients diagnosed with major depression and started on antidepressant pharmacotherapy. Two hundred forty-six depressed patients, diagnosed and treated at one of three outpatient clinics affiliated with the Kaiser-Permanente Northwest Region (KPNW) healthcare system, were randomly assigned to either receive or not receive (usual care) the educational materials by mail. Depression severity and functional impairment affecting patients' quality of life were assessed at baseline and 4, 12, and 30 weeks later. Self-reported impressions of improvement and patient satisfaction with treatment were also assessed at follow-up. Clinical assessment data were obtained using an interactive voice response (IVR) system. Study subjects were compensated $5, $10, $15, and $25 for completing each assessment (Baseline to Week 30, respectively). Upon study completion, prescription fill data of the subjects were extracted from the KPNW Pharmacy System for analysis of medication compliance. Most of the study subjects (63.5%) responded to the pharmacotherapy treatment by study end-point. Few statistically significant differences in either treatment outcomes or duration of medication compliance were found between the treatment groups, and significant differences found were of fairly small magnitude. Patients not receiving the educational materials initially exhibited a more positive response to treatment (Week 4), but this difference did not persist at later follow-ups and was associated with significantly higher relapse rates. A strong time-dose relationship was evident between the duration of the initial treatment episode and treatment outcomes at follow-up, but randomized treatment assignment did not influence the duration of initial medication compliance. Educational programs designed to encourage depressed patients to obtain adequate pharmacotherapy likely provide medical benefits. Such benefits appear to be relatively subtle and methodological differences between studies contribute to inconsistent conclusions concerning observed benefits. The intent of providing time-phased educational materials to patients is to maximize the relevance of such information by synchronizing it with typical recovery processes and issues. This study suggests that additional efforts at engaging patients earlier after the initiation of treatment might be of most benefit.