Early intervention for substance use is critical to improving adolescent outcomes. Studies have found promising results for Screening, Brief Intervention, and Referral to Treatment (SBIRT), but little research has examined implementation. To compare SBIRT implementation in pediatric primary care among trained pediatricians, pediatricians working in coordination with embedded behavioral health care practitioners (BHCPs), and usual care (UC). The study is a 2-year (November 1, 2011, through October 31, 2013), nonblinded, cluster randomized, hybrid implementation and effectiveness trial examining SBIRT implementation outcomes across 2 modalities of implementation and UC. Fifty-two pediatricians from a large general pediatrics clinic in an integrated health care system were randomized to 1 of 3 SBIRT implementation arms; patients aged 12 to 18 years were eligible. Two modes of SBIRT implementation, (1) pediatrician only (pediatricians trained to provide SBIRT) and (2) embedded BHCP (BHCP trained to provide SBIRT), and (3) UC. Implementation of SBIRT (primary outcome), which included assessments, brief interventions, and referrals to specialty substance use and mental health treatment. The final sample included 1871 eligible patients among 47 pediatricians; health care professional characteristics did not differ across study arms. Patients in the pediatrician-only (adjusted odds ratio [AOR],?10.37; 95% CI,?5.45-19.74; P < .001) and the embedded BHCP (AOR,?18.09; 95% CI, 9.69-33.77; P < .001) arms had higher odds of receiving brief interventions compared with patients in the UC arm. Patients in the embedded BHCP arm were more likely to receive brief interventions compared with those in the pediatrician-only arm (AOR,?1.74; 95% CI,?1.31-2.31; P < .001). The embedded BHCP arm had lower odds of receiving a referral compared with the pediatrician-only (AOR,?0.58; 95% CI,?0.43-0.78; P < .001) and UC (AOR,?0.65; 95% CI,?0.48-0.89; P = .006) arms; odds of referrals did not differ between the pediatrician-only and UC arms. The intervention arms had better screening, assessment, and brief intervention rates than the UC arm. Patients in the pediatrician-only and UC arms had higher odds of being referred to specialty treatment than those in the embedded BHCP arm, suggesting lingering barriers to having pediatricians fully address substance use in primary care. Findings also highlight age and ethnic groups less likely to receive these important services. Clinicaltrials.gov Identifier: NCT02408952.