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This pragmatic cluster randomized trial evaluated the effect of an electronic health record (EHR)-integrated clinical decision support system (CDSS) aimed at improving opioid use disorder (OUD) diagnosis and treatment in primary care clinics across multiple US health systems. While the CDSS did not increase OUD diagnosis rates within 30 days, it significantly improved naloxone prescribing and initiation of medications for OUD (MOUD) or specialty referrals. However, MOUD adherence over 90 days and overdose or death rates were unchanged, highlighting the potential and limitations of CDSS in addressing the opioid crisis in primary care.