OBJECTIVE: Chronic low back pain (CLBP) is disabling and costly. Existing therapies have proven suboptimal, with many patients resorting to long-term opioid therapy, which can cause harms. Cognitive behavioral (CBT) and mindfulness-based (MBT) therapies can be effective and offer unique skills for safe pain coping. This article describes the protocol for a study evaluating comparative effectiveness of CBT and MBT in adults with opioid-treated CLBP. DESIGN: Pragmatic, multi-center randomized controlled trial (RCT). SETTINGS: Community and outpatient care. PARTICIPANTS: Planned enrollment of 766 adults (383/group) with CLBP treated with long-term opioids (≥3 months; ≥15 mg/day morphine-equivalent dose). INTERVENTIONS: CBT or MBT consisting of eight weekly therapist-led, two-hour group sessions, and home practice (≥30 min/day, 6 days/week) during the 12-month study. MAIN OUTCOME MEASURES: Main outcome measures, collected by self-report at baseline, then three, six, nine and 12 months post-entry, include co-primary measures: pain intensity (Numeric Rating Scale) and function (Oswestry Disability Index), and secondary measures: quality of life (Medical Outcomes Study) and average daily opioid dose (Timeline Followback). Baseline scores of depression, anxiety, and opioid misuse questionnaires will be assessed as potential contributors to the heterogeneity of treatment response. Intention-to-treat, linear mixed-effects analysis will examine treatment effectiveness. Qualitative data will augment the quantitative measures. CONCLUSIONS: This will be the largest RCT comparing CBT and MBT in opioid-treated CLBP. It will provide evidence on the impact of these interventions, informing clinical decisions about optimal therapy for safe, effective care, improving quality of life and decreasing opioid-related harm among adults with refractory CLBP.