<h3>Importance</h3> Although brief intervention is effective for reducing problem alcohol use, few data exist on its effectiveness for reducing problem drug use, a common issue in disadvantaged populations seeking care in safety-net medical settings (hospitals and community health clinics serving low-income patients with limited or no insurance). <h3>Objective</h3> To determine whether brief intervention improves drug use outcomes compared with enhanced care as usual. <h3>Design, Setting, and Participants</h3> A randomized clinical trial with blinded assessments at baseline and at 3, 6, 9, and 12 months conducted in 7 safety-net primary care clinics in Washington State. Of 1621 eligible patients reporting any problem drug use in the past 90 days, 868 consented and were randomized between April 2009 and September 2012. Follow-up participation was more than 87% at all points. <h3>Interventions</h3> Participants received a single brief intervention using motivational interviewing, a handout and list of substance abuse resources, and an attempted 10-minute telephone booster within 2 weeks (n = 435) or enhanced care as usual, which included a handout and list of substance abuse resources (n = 433). <h3>Main Outcomes and Measures</h3> The primary outcomes were self-reported days of problem drug use in the past 30 days and Addiction Severity Index–Lite (ASI) Drug Use composite score. Secondary outcomes were admission to substance abuse treatment; ASI composite scores for medical, psychiatric, social, and legal domains; emergency department and inpatient hospital admissions, arrests, mortality, and human immunodeficiency virus risk behavior. <h3>Results</h3> Mean days used of the most common problem drug at baseline were 14.40 (SD, 11.29) (brief intervention) and 13.25 (SD, 10.69) (enhanced care as usual); at 3 months postintervention, means were 11.87 (SD, 12.13) (brief intervention) and 9.84 (SD, 10.64) (enhanced care as usual) and not significantly different (difference in differences, β = 0.89 [95% CI, −0.49 to 2.26]). Mean ASI Drug Use composite score at baseline was 0.11 (SD, 0.10) (brief intervention) and 0.11 (SD, 0.10) (enhanced care as usual) and at 3 months was 0.10 (SD, 0.09) (brief intervention) and 0.09 (SD, 0.09) (enhanced care as usual) and not significantly different (difference in differences, β = 0.008 [95% CI, −0.006 to 0.021]). During the 12 months following intervention, no significant treatment differences were found for either variable. No significant differences were found for secondary outcomes. <h3>Conclusions and Relevance</h3> A one-time brief intervention with attempted telephone booster had no effect on drug use in patients seen in safety-net primary care settings. This finding suggests a need for caution in promoting widespread adoption of this intervention for drug use in primary care. <h3>Trial Registration</h3> clinicaltrials.gov Identifier:NCT00877331

Brief Intervention for Problem Drug Use in Safety-Net Primary Care Settings