Abstract: Objective: Brief cognitive behavior therapy (bCBT) is effective in reducing symptoms of depression and anxiety disorders and improving health-related quality of life (HRQoL). However, the mechanisms through which cognitive behavior therapy impact HRQoL are not well understood. This study evaluated whether anxiety and depression symptom reduction is a mechanism of treatment for HRQoL outcomes. Method: Using secondary data from a multisite, pragmatic, randomized trial, this study evaluated bCBT vs enhanced usual care in 16 VA community-based outpatient clinics. Ordinary least-squares path analysis testing multiple mediators was used to evaluate the role of change in depression and anxiety symptoms in the relationship between treatment condition and HRQoL. Results: Receiving bCBT (vs. enhanced usual care) was significantly negatively associated with change (reduction) in depression and anxiety scores. The indirect effect of treatment on mental HRQoL was significant with change in depression scores as mediator. A similar pattern was observed for physical HRQoL and change in anxiety scores as mediator. Conclusion: Findings suggest reduction of depression and anxiety symptoms as a mechanism through which bCBT for depression promoted improvements in HRQoL, with important implications for understanding how CBT impacts functioning, as well as the utility of bCBT in nontraditional mental health settings.