Background: Advanced heart failure therapies such as left ventricular assist device (LVAD) implantation require intricate follow-up and complex care. We sought to explore the burden of psychosocial risk factors among patients with LVAD and their impact on postimplant outcomes using the Interagency Registry for Mechanically Assisted Circulatory Support. Methods: Adult patients in the Interagency Registry for Mechanically Assisted Circulatory Support requiring durable LVAD between 2008 and 2017 were included. Individuals were determined to have psychosocial risk if they had one of the following: (1) limited social support; (2) limited cognition; (3) substance abuse (alcohol and drug); (4) severe psychiatric disease (including major depression and other major psychiatric diagnosis); and (5) repeated noncompliance. Univariate and multivariate Cox proportional hazard regression models were used to analyze predictors of survival and complications. Results: A total of 15 403 continuous-flow LVAD recipients were included. A total of 3163 (20.5%) had one or more psychosocial risk factors. The most prevalent psychosocial risk factor was substance abuse in 1941 (12.6%) recipients. Patients with psychosocial risk factors were significantly younger at LVAD implant, less likely to be White, and less likely to be female compared with those without psychosocial risk, P <0.001 for all. Patients with psychosocial risk were significantly more likely to receive an LVAD as destination therapy, P <0.001. In adjusted models, patients with psychosocial risk were at increased hazards for device-related infection, gastrointestinal bleeding, pump thrombosis, and readmission and reduced hazards for cardiac transplantation ( P <0.05 for all). There was no statistically significant difference in survival on pump support or stroke. Conclusions: Psychosocial risk is an important component of patient selection for advanced heart failure therapies. Addressing these specific components may help improve access to advanced therapies and post-LVAD outcomes.