OBJECTIVES Although brief interventions (BIs) have shown some success for smoking cessation and alcohol misuse, it is not known if they can be applied in the emergency department (ED) to drug use and misuse. The objectives of this investigation were to assess the 3-month efficacy of a BI to reduce drug use and misuse, increase drug treatment services utilization among adult ED patients, and identify subgroups more likely to benefit from the BI. METHODS This randomized, controlled trial enrolled 18- to 64-year-old English- or Spanish-speaking patients from two urban, academic EDs whose responses to the Alcohol, Smoking, and Substance Involvement Screening Test indicated a need for a brief or intensive intervention. Treatment participants received a tailored BI, while control participants only completed the study questionnaires. At the 3-month follow-up, each participant's past 3-month drug use and misuse and treatment utilization were compared to his or her baseline enrollment data. Regression modeling was used to identify subgroups of patients (per demographic and clinical factors) more likely to stop or reduce their drug use or misuse or engage in drug treatment by the 3-month follow-up assessment. RESULTS Of the 1,030 participants, the median age was 30 years (interquartile range = 24 to 42 years), and 46% were female; 57% were white/non-Hispanic, 24.9% were black/non-Hispanic, and 15% were Hispanic. The most commonly misused drugs were marijuana, prescription opioids, cocaine/crack, and benzodiazepines. Although at follow-up the proportions of participants reporting any past 3-month drug misuse had decreased in both study arms (control 84% vs. treatment 78%), the decreases were similar between the two study arms (Δ-6.3%; 95% confidence interval [CI] = -13.0% to 0.0). In addition, at follow-up there were no differences between study arms in those who were currently receiving drug treatment (Δ1.8; 95% CI = -3.5 to 6.8), who had received treatment during the past 3 months (Δ-2.0; 95% CI = -6.5 to 2.4), or who at least contacted a treatment program (Δ 1.7; 95% CI = -2.4 to 6.1). Those whose baseline screening indicated the need for a brief instead of a more intensive intervention, and those currently engaged in drug treatment at the 3-month follow-up, were generally more likely to stop or decrease their drug use/misuse. CONCLUSIONS The BI employed in this study did not reduce drug use and misuse or increase treatment utilization more than the control condition over a 3-month period. Future research should help determine what role, if any, BIs should play in affecting drug use and misuse among ED patients.