OBJECTIVES: Deficits in physical health-related quality of life (HRQL) and sleep quality in chronic low back pain (CLBP) patients may be alleviated with Buprenorphine Transdermal System (BTDS) treatment. This post-hoc analysis of clinical trial data aimed to explore whether BTDS treatment has a direct impact on HRQL and sleep quality, an indirect impact on the outcomes as mediated through its impact of pain, or both; and to identify significant correlates of HRQL and sleep quality. METHODS: In this multicenter, enriched, double-blind, randomized trial, opioid-naïve patients with moderate-to-severe CLBP received twelve weeks’ treatment with BTDS (10 or 20 mcg/hour) or placebo. A series of multivariate linear regression models (stepwise) predicting physical HRQL, sleep disturbance, and sleep quality at week 12 were fitted. Physical HRQL was measured using the SF-36v2 Physical Component Summary (PCS), while sleep outcomes were measured using the Disturbance subscale and Sleep Problems Index (SPI) of the Medical Outcomes Study Sleep Scale (MOS-SS).  For each outcome, models 1 and 2 included baseline demographic and clinical variables, model 3 added treatment arm, and model 4 added pain assessment at week 8. RESULTS: Results from model 3 supported BTDS treatment as a significant predictor of better physical HRQL and sleep outcomes. Model 4 results for each outcome indicated that pain was a partial mediator of treatment on physical HRQL and sleep quality, meaning that treatment had both direct and indirect effects on these outcomes. Mid-trial pain and the baseline value of the outcome being tested (i.e., PCS score, Disturbance score, or SPI score) were the strongest predictors for each outcome. CONCLUSIONS: For CLBP patients, improvements in physical HRQL, sleep disturbance, and sleep quality were impacted by BTDS treatment both directly as well as indirectly via mediation through the treatment-driven reductions in pain. Mid-trial pain strongly predicted to HRQL and sleep outcomes.