Importance Patient outcomes in heart failure clinical trials are generally better than those observed in real-world settings. This may be related to stricter inclusion and exclusion criteria in clinical trials. Objective We study sought to characterize the clinical implications of differences between patients in clinical trials and those in a real-world registry of patients receiving left ventricular assist devices (LVADs). Design, setting, and participants This retrospective cohort study included all patients in INTERMACS (the Interagency Registry for Mechanically Assisted Circulatory Support) who were implanted with an axial flow LVAD from 2010 to 2015 to allow for equivalent comparisons. Main outcomes and measures Differences in patient characteristics and 2-year rates of adverse outcomes with those reported in the ENDURANCE and MOMENTUM 3 clinical trials. Survival analyses were used to assess the relationships between prespecified patient factors and clinical outcomes. Results Of the 10,937 LVAD recipients identified in INTERMACS between 2010–2015, 44% met at least 1 clinical trial exclusion criterion. The 2-year incidence of stroke and death amongst LVAD recipients in INTERMACS and the landmark clinical trials differed significantly (P<0.04, both). Nevertheless, patients who would have been excluded from the clinical trials did not have dramatically different 2-year mortality outcomes in INTERMACS [2y survival estimate: 66.4%, 95% CI (64.9–67.9%) versus 71.9%, 95% CI (70.6–73.1%)]. Clinical interventions driving a significantly increased risk of death were relatively rare (<5% of implants) and included mechanical ventilation, ECMO, severe thrombocytopenia, and dialysis. Conclusions and relevance Most exclusion criteria used in LVAD clinical trials did not afford a substantially greater risk to patients in the real-world setting. In the relatively infrequent cases of end stage renal disease, thrombocytopenia, respiratory failure, and need for ECMO, the risks and benefits of LVAD therapy need careful weighting and further study.