Background To evaluate changes in patient characteristics and outcomes for infective endocarditis (IE) related to opioid use disorder (OUD), we used the National (Nationwide) Inpatient Sample (NIS) to characterize the trend in hospitalizations for patients with IE with and without OUD and those treated medically and surgically. Methods and Results Temporal trends in hospitalization characteristics for patients with IE with and without OUD and those treated medically and surgically were estimated via the NIS data in 2005-2014. Hospitalizations for OUD and IE increased from 119 to 202 and from 12 to 15 cases per 100 000 between 2005 and 2014, respectively. Hospitalizations with OUD among all IE hospitalizations increased from 6.3% in 2005 to 11.6% in 2014. Among all IE hospitalizations, patients being admitted for IE in the setting of OUD were younger compared with the cohort of IE without OUD (aged 37.6±0.21 years versus 60.9±0.16 years). Myocardial infarction, diabetes mellitus, chronic kidney disease, peripheral vascular disease, and heart failure were more common in patients without OUD. The OUD cohort more frequently had liver disease (46.0% versus 10.8%) and immunosuppressed status (4.3% versus 2.1%). Valve operations for IE accounted for 10.2% of all valve operations in 2005, and this increased to 12.7% in 2014. These proportions were similar between OUD (11.4%) and non-OUD (11.1%) cohorts. Operative mortality was lower in patients with OUD (4.3% versus 9.4%, <0.001). Conclusions IE associated with OUD has a distinct phenotype and has become more prevalent. Surgical outcomes are favorable and operations were performed in similar proportions of patients who had IE with OUD compared with patients who had IE without OUD.