OBJECTIVE: This randomized clinical trial evaluated the efficacy of Mindfulness-Oriented Recovery Enhancement (MORE) among past and present U.S. military personnel with prescriptions for long-term opioid therapy for chronic pain. METHODS: In this clinical trial, 230 past and present military personnel with prescriptions for long-term opioid therapy were randomized in a 1:1 ratio to MORE or supportive psychotherapy (initially delivered in person and then via videoconferencing after the onset of the COVID-19 pandemic). Primary outcomes were chronic pain, measured by the Brief Pain Inventory, and aberrant drug-related behaviors, measured by the Current Opioid Misuse Measure, through 8 months of follow-up. Opioid dose was a key secondary outcome. Other outcomes included psychiatric symptoms, catastrophizing, positive affect, ecological momentary assessments of opioid craving, and opioid attentional bias. RESULTS: MORE was superior to supportive psychotherapy through the 8-month follow-up in reducing pain-related functional interference, pain severity, and opioid dose. MORE reduced daily opioid dose by 20.7%, compared with a dose reduction of 3.9% with supportive psychotherapy. Although there was no overall between-group difference in opioid misuse, the in-person MORE intervention outperformed supportive psychotherapy for reducing opioid misuse. MORE reduced anhedonia, pain catastrophizing, craving, and opioid attentional bias and increased positive affect to a greater extent than supportive psychotherapy. MORE also modulated therapeutic processes, including mindful reinterpretation of pain sensations, nonreactivity, savoring, positive attention, and reappraisal. CONCLUSIONS: Among past and present U.S. military personnel, MORE led to sustained decreases in chronic pain, opioid use, craving, and opioid cue reactivity. MORE facilitated opioid dose reduction while preserving adequate pain control and preventing mood disturbances, suggesting its utility for safe opioid tapering.