Background: A growing number of Veterans are presenting to the Veterans Health Administration (VHA) for the treatment of Bipolar disorder (BP) and co-occurring substance use disorders (SUDs), with prevalence of SUDs in patients with BP up to 60%. This comorbidity is associated with increased symptom severity, poorer treatment outcomes, and greater use of costly health services such as psychiatric hospitalization. Significance/Impact: Veterans who transition from psychiatric hospitalization to outpatient care are at heightened risk for treatment nonadherence, mood/substance relapse, deaths due to opioid overdose, and suicide. Nonadherence to treatment is a significant problem among patients with BP, which is further magnified among those with SUDs. Nonadherence leads to increased need for psychiatric readmission, with BP patients recently discharged from inpatient care particularly likely to discontinue pharmacotherapy, relapse to substances, and attempt suicide. Of particular concern are disproportionately greater rates of suicide in Veterans with BP relative to those with other mental health conditions. Veterans with BP who use substances, particularly alcohol and opioids, have the highest suicidality and mortality rates. To date, there is little research on effective and feasible behavioral aftercare interventions designed to improve treatment adherence in this high-risk, comorbid population at the critical period following hospital discharge. Innovation: Empirical work suggests that the “Integrated Treatment Adherence Program” (ITAP) may be an ideal therapeutic approach to improve treatment adherence and clinical outcomes in Veterans at the critical period of transition to outpatient care following hospitalization. ITAP is an innovative psychosocial intervention developed by our team designed to improve treatment adherence and reduce suicidality, bipolar symptoms, and substance abuse among high-risk patients, addressing HSR&D major research priorities. ITAP combines in-person engagement sessions with follow-up phone contacts and significant other involvement as an adjunct to treatment as usual over 6 months post-hospitalization. Methodology: The proposed Hybrid Type 1 Effectiveness-Implementation Trial will evaluate the effectiveness of ITAP in a sample of 140 Veterans with BP-SUD, randomized to receive either the ITAP intervention or a Safety Assessment and Follow-up Evaluation (SAFE) comparison condition, both delivered as adjuncts to VHA treatment as usual. Veterans will be recruited from the Providence VAMC inpatient psychiatric unit and assessed at baseline and at 3 (mid-treatment), 6 (post-treatment), and 9-month follow-up. The Primary Aim is to test the hypotheses that participants randomized to receive ITAP, relative to SAFE, will evidence improved treatment outcomes at post- treatment, maintained through follow-up. Primary outcomes are: 1) greater treatment adherence defined by (a) percent missed medications doses/month (based on elec...