Importance: Medication management and cognitive behavioral therapy (CBT) are commonly used treatments for chronic low back pain (CLBP). However, little evidence is available comparing the effectiveness of these approaches. Objective: To compare collaborative care medication optimization vs CBT on pain intensity, interference, and other pain-related outcomes. Design, Setting, and Participants: The Care Management for the Effective Use of Opioids (CAMEO) trial was a 12-month, comparative effectiveness randomized clinical trial with blinded outcome assessment. Recruitment of veterans with CLBP prescribed long-term opioids occurred at 7 Veterans Affairs primary care clinics from September 1, 2011, to December 31, 2014, and follow-up was completed December 31, 2015. Analyses were based on intention to treat in all randomized participants and were performed from March 22, 2015, to November 1, 2021. Interventions: Patients were randomized to receive either collaborative care with nurse care manager-delivered medication optimization (MED group) (n = 131) or psychologist-delivered CBT (CBT group) (n = 130) for 6 months, with check-in visits at 9 months and final outcome assessment at 12 months. Main Outcomes and Measures: The primary outcome was change in Brief Pain Inventory (BPI) total score, a composite of the pain intensity and interference subscales at 6 (treatment completion) and 12 (follow-up completion) months. Scores on the BPI range from 0 to 10, with higher scores representing greater pain impact and a 30% improvement considered a clinically meaningful treatment response. Secondary outcomes included pain-related disability, pain catastrophizing, self-reported substance misuse, health-related quality of life, depression, and anxiety. Results: A total of 261 patients (241 [92.3%] men; mean [SD] age, 57.9 [9.5] years) were randomized and included in the analysis. Baseline mean (SD) BPI scores in the MED and CBT groups were 6.45 (1.79) and 6.49 (1.67), respectively. Improvements in BPI scores were significantly greater in the MED group at 12 months (between-group difference, -0.54 [95% CI, -1.18 to -0.31]; P = .04) but not at 6 months (between-group difference, -0.46 [95% CI, -0.94 to 0.11]; P = .07). Secondary outcomes did not differ significantly between treatment groups. Conclusions and Relevance: In this randomized clinical trial among US veterans with CLBP who were prescribed long-term opioid therapy, collaborative care medication optimization was modestly more effective than CBT in reducing pain impact during the 12-month study. However, this difference may not be clinically meaningful or generalize to nonveteran populations. Trial Registration: ClinicalTrials.gov Identifier: NCT01236521.