BackgroundOpioid overdose deaths occur in civilian and military populations and are the leading cause of accidental death in the USA.ObjectiveTo determine whether ECHO Pain telementoring regarding best practices in pain management and safe opioid prescribing yielded significant declines in opioid prescribing.DesignA 4-year observational cohort study at military medical treatment facilities worldwide.ParticipantsPatients included 54.6% females and 46.4% males whose primary care clinicians (PCCs) opted to participate in ECHO Pain; the comparison group included 39.9% females and 60.1% males whose PCCs opted not to participate in ECHO Pain.InterventionPCCs attended 2-h weekly Chronic Pain and Opioid Management TeleECHO Clinic (ECHO Pain), which included pain and addiction didactics, case-based learning, and evidence-based recommendations. ECHO Pain sessions were offered 46 weeks per year. Attendance ranged from 1 to 3 sessions (47.7%), 4–19 (32.1%, or > 20 (20.2%).Main MeasuresThis study assessed whether clinician participation in Army and Navy Chronic Pain and Opioid Management TeleECHO Clinic (ECHO Pain) resulted in decreased prescription rates of opioid analgesics and co-prescribing of opioids and benzodiazepines. Measures included opioid prescriptions, morphine milligram equivalents (MME), and days of opioid and benzodiazepine co-prescribing per patient per year.Key ResultsPCCs participating in ECHO Pain had greater percent declines than the comparison group in (a) annual opioid prescriptions per patient (− 23% vs. − 9%, P < 0.001), (b) average MME prescribed per patient/year (−28% vs. −7%, p < .02), (c) days of co-prescribed opioid and benzodiazepine per opioid user per year (−53% vs. −1%, p < .001), and (d) the number of opioid users (−20.2% vs. −8%, p < .001). Propensity scoring transformation–adjusted results were consistent with the opioid prescribing and MME results.ConclusionsPatients treated by PCCs who opted to participate in ECHO Pain had greater declines in opioid-related prescriptions than patients whose PCCs opted not to participate.Electronic supplementary materialThe online version of this article (10.1007/s11606-018-4710-5) contains supplementary material, which is available to authorized users.