This study compares the clinical course of tricyclic antidepressant and fluoxetine overdose. The study was a prospective case series of 9 urban hospital systems. Consecutive sampling of overdose patients presenting to emergency departments provided the participants for the study. The therapy was determined by each institution. Clinical, laboratory, economic impact, and coroners' information was gathered. Of 622 patients, 482 were excluded because of significant coingestants or lack of laboratory confirmation, leaving 124 tricyclic antidepressant and 16 fluoxetine cases. Twenty-seven percent of tricyclic antidepressant patients were alert on arrival to the emergency department; only 12.9% remained alert. The following were significantly more frequent after tricyclic antidepressant overdose: agitation, tachycardia, QRS prolongation, terminal R-wave deviation, intubation, coma, and admission to the intensive care unit. The mean tricyclic plus metabolite level was 777.6 ng/mL (range = 20-5260 ng/ mL), and the mean fluoxetine plus metabolite level was 496.4 ng/mL (range = 120-1930 ng/mL). There were two tricyclic antidepressant deaths. Of 179 total drug-ingestion deaths from the coroners' records, 38 were from tricyclic antidepressants and none from fluoxetine. Thus, tricyclic antidepressant overdoses resulted in more toxicity and more frequent admissions to the intensive care unit than did fluoxetine overdoses.