Loneliness—a subjective emotional state characterized by the perception of social isolation—is a psychosocial stressor that is associated with increased mortality, opioid use, and is associated with precipitants of relapse among individuals with opioid use disorders (OUDs). Importantly, there are effective interventions that can be used to decrease loneliness; however, there are no studies that have directly intervened on loneness among individuals with OUDs, and the mechanisms by which loneliness impacts opioid use need to be elucidated. Cognitive-Behavioral Therapy for Loneliness (CBT-L) intervenes on loneliness by addressing negative beliefs that perpetuate loneliness, increase negative affect, and reduce one’s ability to engage in social activities. For an individual with an OUD, this is critical as addressing negative affect, and having a sense that one has social support and engages social support are key aspects of recovery. The proposed two-year study uses a novel application of a brief, phone-delivered, evidence-based intervention, CBT-L, to decrease loneliness by modifying maladaptive thinking behaviors, increasing engagement in enjoyable and social activities, and improving problem solving skills over just 4 session delivered by phone. Participants will be recruited nationally using online and print advertising. The specific aims are to: (1) assess the efficacy of CBT-L’s impact, relative to an education control, on loneliness, negative affect, and the quality and quantity of social interactions among 125 people with an OUD, and (2) assess the cognitive, affective, and behavioral mechanisms of the impact of CBT-L on opioid use trajectories. We expect that CBT-L will reduce loneliness, negative affect, and the quality and quantity of social interactions, thereby reducing opioid use. This R21 application is in response to PAS-18- 625, Mechanistic investigations of psychosocial stress effects on opioid use patterns sponsored by NIDA. The study team is ideally suited to conduct this research given their extensive experience in conducting research and doing clinical work in individuals with opioid use disorders, clinical trial experience with CBT for a variety of difficult-to-reach and treat individuals, and ability to recruit and retain often treatment-resistant people, including those with substance use disorders. Results from this study will provide critical information to conduct a fully-powered efficacy trial and assessment of cognitive and affective mechanisms of the link between loneliness and OUD.