IMPORTANCE: Methadone treatment (MT) fails to address the emotion dysregulation, pain, and reward processing deficits that often drive opioid use disorder (OUD). New interventions are needed to address these factors. OBJECTIVE: To evaluate the efficacy of MT as usual (usual care) vs telehealth Mindfulness-Oriented Recovery Enhancement (MORE) plus usual care among people with an OUD and pain. DESIGN, SETTING, AND PARTICIPANTS: This study was a randomized clinical trial conducted from August 2020 to June 2022. Participants receiving MT for OUD and experiencing chronic pain were recruited at 5 clinics in New Jersey. INTERVENTIONS: In usual care, participants received MT, including medication and counseling. Participants receiving MORE plus usual care attended 8 weekly, 2-hour telehealth groups that provided training in mindfulness, reappraisal, and savoring in addition to usual care. MAIN OUTCOMES AND MEASURE: Primary outcomes were return to drug use and MT dropout over 16 weeks. Secondary outcomes were days of drug use, methadone adherence, pain, depression, and anxiety. Analyses were based on an intention-to-treat approach. RESULTS: A total of 154 participants (mean [SD] age, 48.5 [11.8] years; 88 female [57%]) were included in the study. Participants receiving MORE plus usual care had significantly less return to drug use (hazard ratio [HR], 0.58; 95% CI, 0.37-0.90; P = .02) and MT dropout (HR, 0.41; 95% CI, 0.18-0.96; P = .04) than those receiving usual care only after adjusting for a priori-specified covariates (eg, methadone dose and recent drug use, at baseline). A total of 44 participants (57.1%) in usual care and 39 participants (50.6%) in MORE plus usual care returned to drug use. A total of 17 participants (22.1%) in usual care and 10 participants (13.0%) in MORE plus usual care dropped out of MT. In zero-inflated models, participants receiving MORE plus usual care had significantly fewer days of any drug use (ratio of means = 0.58; 95% CI, 0.53-0.63; P < .001) than those receiving usual care only through 16 weeks. A significantly greater percentage of participants receiving MORE plus usual care maintained methadone adherence (64 of 67 [95.5%]) at the 16-week follow-up than those receiving usual care only (56 of 67 [83.6%]; χ2 = 4.49; P = .04). MORE reduced depression scores and ecological momentary assessments of pain through the 16-week follow-up to a significantly greater extent than usual care (group × time F2,272 = 3.13; P = .05 and group × time F16,13000 = 6.44; P < .001, respectively). Within the MORE plus usual care group, EMA pain ratings decreased from a mean (SD) of 5.79 (0.29) at baseline to 5.17 (0.30) at week 16; for usual care only, pain decreased from 5.19 (0.28) at baseline to 4.96 (0.29) at week 16. Within the MORE plus usual care group, mean (SD) depression scores were 22.52 (1.32) at baseline and 18.98 (1.38) at 16 weeks. In the usual care-only group, mean (SD) depression scores were 22.65 (1.25) at baseline and 20.03 (1.27) at 16 weeks. Although anxiety scores increased in the usual care-only group and decreased in the MORE group, this difference between groups did not reach significance (group × time unadjusted F2,272 = 2.10; P= .12; Cohen d = .44; adjusted F2,268 = 2.33; P = .09). Within the MORE plus usual care group, mean (SD) anxiety scores were 25.5 (1.60) at baseline and 23.45 (1.73) at 16 weeks. In the usual care-only group, mean (SD) anxiety scores were 23.27 (1.75) at baseline and 24.07 (1.73) at 16 weeks. CONCLUSIONS AND RELEVANCE: This randomized clinical trial demonstrated that telehealth MORE was a feasible adjunct to MT with significant effects on drug use, pain, depression, treatment retention, and adherence. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04491968.