Objective: For individuals in alcohol use disorder (AUD) treatment, many argue that holistic indicators such as quality of life (QoL) should be more consistently used in addition to drinking-related indicators. QoL increases from pre- to post-AUD treatment, but the mechanisms are unclear. The present study examined the roles of positive and negative affect in QoL change during AUD treatment and additionally explored the relationship between QoL change and medication adherence. Method: We examined the mediating roles of end-of-treatment positive affect (i.e., vigor) and negative affect (i.e., stress and tension) in the relationship between baseline (BL) and 26-week QoL among participants in the Combined Pharmacotherapies and Behavioral Interventions for Alcohol Dependence study randomized to medication management (MM; n = 468) or medication management plus combined behavioral intervention (MMCBI; n = 479) for AUD. We also explored whether changes in QoL were associated with medication adherence. Results: Change in psychological health QoL was mediated by increased vigor (i.e., positive affect) and decreased stress, and change in environmental QoL was mediated by decreased stress. There were also differences by treatment group, with stress mediating changes in environmental QoL among participants in MM, and vigor mediating changes in psychological health QoL among participants in MMCBI. Medication adherence was not associated with greater QoL after controlling for posttreatment alcohol use. Conclusions: The present study identified potential mechanisms of QoL change in AUD treatment, thus contributing to the growing knowledge surrounding alternative indicators of treatment success for AUD treatment and recovery. Targeting affective states and stress during treatment may improve QoL and recovery outcomes for persons with AUD. (PsycInfo Database Record (c) 2022 APA, all rights reserved)