IMPORTANCE: Chronic low back pain (CLBP) can necessitate opioid therapy. Effective approaches to reduce CLBP's symptoms and opioid-related harms are needed. Cognitive behavioral (CBT) and mindfulness-based (MBT) therapies may be useful but have not been well-studied for opioid-treated CLBP. OBJECTIVE: To compare the effectiveness of MBT vs CBT in opioid-treated CLBP, hypothesizing MBT's superiority. DESIGN, SETTING, AND PARTICIPANTS: In this 12-month community partner-informed, partially masked, multisite, randomized clinical trial, participants at primary and specialty care clinics and community settings were randomly assigned (1:1) to MBT or CBT groups. Participants included English-fluent adults (21 years or older), without prior MBT or CBT training, and with moderate-to-severe CLBP (average score ≥3 on the Brief Pain Inventory [BPI]; functional limitation score ≥20 on the Oswestry Disability Index [ODI]), treated with an opioid dosage of at least 15 mg/d of morphine milligram equivalents (MME) for at least 3 months. Outcome data were collected from July 1, 2017, to November 23, 2022. Analysis used the intention-to-treat approach. INTERVENTIONS: Manual-based MBT or CBT interventions consisting of 8 weekly therapist-led group sessions and at-home practice. OUTCOMES AND MEASURES: Self-reported coprimary (average pain severity, 0-10 [BPI]; functional limitations, 0-100 [ODI]) and secondary (mental and physical health-related quality of life [QOL] on the Medical Outcomes Study 12-Item Short Form Health Survey and opioid dose in MME per day, Timeline Followback) outcomes compared at 6 and 12 months. RESULTS: Among 6024 screened individuals, 2926 were ineligible, 2328 were eligible, and 770 were enrolled, including 385 in the MBT and 385 in the CBT groups. Of these, 434 participants (56.4%) were female, 647 (84.0%) identified as non-Hispanic ethnicity, and 630 (81.8%) identified as White race; mean (SD) age was 57.8 (11.3) years. The mean (SD) BPI average pain score was 6.1 (1.6) (moderate pain) and the mean (SD) ODI functional limitation score was 47.2 (14.0) (moderate functional limitations), with reduced physical (mean [SD], 28.5 [8.3]) and mental (mean [SD], 42.5 [11.8]) health-related QOL on the SF-12 and high opioid dosage (mean [SD], 177 [1041] MME/d). Over time, each group significantly improved their outcomes, without serious adverse effects. The intention-to-treat linear mixed-effects model analysis did not detect significant between-group differences at 6 and 12 months for pain (0.21 [95% CI, -0.05 to 0.48; P = .12] and 0.13 [95% CI, -0.13 to 0.40; P = .33], respectively) or function (0.07 [95% CI, -1.80 to 1.93; P = .94], and 0.27 [95% CI, -1.59 to 2.12; P = .78], respectively) and indicated MBT's noninferiority relative to CBT on primary outcomes. CONCLUSIONS AND RELEVANCE: In this large trial, CLBP-related symptoms improved, while opioid dosage decreased in both MBT and CBT groups at 6 and 12 months. Increasing availability of these safe psychological therapies could help reduce individual and societal burdens of refractory, opioid-treated CLBP. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03115359.