To determine the clinical predictors and rate of relapse for major depression in primary care. A cohort study of subjects in 2 randomized trials of depressed patients diagnosed and prescribed antidepressant medicine by primary care physicians. Baseline, 7-month, and 19-month assessments were conducted. A large primary care clinic of a staff-model health maintenance organization. Two hundred fifty-one primary care patients who did not satisfy Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition (DSM-III-R) criteria for major depression at 7 months. Relapse was defined as (1) satisfying DSM-III-R criteria for major depression at 19 months, or (2) reporting an interval episode of 2 weeks or more of depressed mood and symptoms between 7 and 19 months. Predictors examined included demographic characteristics, medical comorbidity, disability, and psychological symptoms. Depressive symptoms were measured by Inventory of Depressive Symptoms and Hopkins Symptoms Checklist. Of the patients, 37.1% reported relapse of depression in the 12-month relapse-risk period. The 2 major risk factors associated with relapse were (1) persistence of subthreshold depressive symptoms 7 months after the initiation of antidepressant therapy (odds ratio, 3.3; 95% confidence interval, 2.74-3.93) and (2) history of 2 or more episodes of major depression, or chronic mood symptoms for 2 years (odds ratio, 2.1; 95% confidence interval, 1.41-2.76). Patients with both risk factors were approximately 3 times more likely to relapse than patients with neither. The relapse rate among primary care patients treated for depression approached that of specialty samples, with more than one third reporting relapse in 1 year. Clinical characteristics can help target high-risk patients for relapse prevention efforts.