This study was undertaken to evaluate the clinical utility and cost-effectiveness of the limited component versus the high performance liquid chromatography (HPLC) component of comprehensive toxicologic screens in children. A retrospective patient series was studied at the emergency department (ED) of Hughes Spalding Children's Hospital, an urban, tertiary-care ED, consisting of all patients younger than 19 years of age who had a comprehensive toxicologic screen between January 1994 and July 1995. The comprehensive test included a broad-spectrum HPLC component as well as a limited component that examined serum for ethanol, aspirin, and acetaminophen and urine for benzodiazepines, barbiturates, amphetamines, cocaine, phencyclidine, and opiates. All toxicologic screens were reviewed for the presence of exogenous toxins, followed by a chart review of all patients with positive screens and a selection of negative screens. Toxins were categorized as (1) iatrogenic or noniatrogenic, (2) clinically or nonclinically suspected by history and physical, and (3) clinically or nonclinically significant. Comprehensive toxicology screens were performed in 463 cases during the study period; 234 (51%) were positive for exogenous toxins. In 227 of 234 positive screens (97%), toxins were either suspected by history and/or physical, were present on the limited portion of the toxicology screen, or were clinically insignificant. The remaining 7 of the 234 positive screens (3%) were clinically significant and detected solely by the broad-spectrum HPLC portion of the comprehensive screen. However, in none of these 7 cases was patient management clinically altered as a result of the positive screen. The total additional cost for the HPLC component was $16,205 ($35x463), an average distributive charge of $2,315 per patient in whom the HPLC portion provided additional clinical information ($16,205/7). Although adding significant charges to the evaluation of suspected toxic exposures in children, the HPLC component of the comprehensive drug screen was of no additional clinical benefit compared with its limited component alone.