To compare the long-term clinical, quality-of-life, and economic outcomes after an initial prescription for fluoxetine, imipramine hydrochloride, or desipramine hydrochloride. Randomized, controlled trial. Primary care clinics of a staff-model health maintenance organization in the Seattle, Wash, area. Four hundred seventy-one adults beginning antidepressant drug treatment for depression. Random assignment of initial medication (desipramine, fluoxetine, or imipramine), with treatment (dosing, medication changes or discontinuation, and follow-up visits) managed by a primary care physician. Interviews at baseline and at 6, 9, 12, 18, and 24 months examined medication use, clinical outcomes (Hamilton Depression Rating Scale and depression subscale of the Hopkins Symptom Checklist), and quality of life (Medical Outcomes Study SF-36 Health Survey). Medical costs were assessed using the health maintenance organization's accounting data. Patients assigned to fluoxetine therapy were significantly more likely to continue taking the initial antidepressant but no more likely to continue any antidepressant therapy. The fluoxetine group did not differ significantly from either tricyclic drug group on any measure of depression severity or quality of life. For 24 months, antidepressant drug costs were approximately $250 higher for patients assigned to fluoxetine therapy, but total medical costs were essentially identical. Initial selection of fluoxetine or a tricyclic antidepressant drug should lead to similar clinical outcomes, functional outcomes, and overall costs. Differences in antidepressant prescription costs are blunted by the large minority of tricyclic-treated patients who switch to use of more expensive medications. Restrictions on first-line use of fluoxetine in primary care will probably not reduce overall treatment costs.