BACKGROUND: The rise in the number of valve operations performed for infective endocarditis (IE) due to drug use is an important manifestation of the opioid epidemic. This study characterized national trends and outcomes of valve surgery for drug use-associated IE (DU-IE). METHODS: Adults undergoing valve surgery for active IE in The Society of Thoracic Surgeons (STS) Adult Cardiac Surgery Database between July 2011 and June 2018 were stratified as DU-IE and non-DU-IE. Trends and clinical profiles were analyzed. Early outcomes were assessed. The association of DU-IE with outcomes was analyzed with multivariable regression, adjusting for STS Valve Risk model covariates. RESULTS: There were 34,905 valve operations performed for IE, of which 33.7% were for DU-IE. DU-IE operations increased 2.7-fold during the study period. There was considerable regional variability in DU-IE operations, ranging from 28% to 58% of all IE surgeries in 2018, with highest rates observed in East South Central and South Atlantic regions. DU-IE patients were younger and had fewer cardiovascular comorbidities. Risk-adjusted major morbidity and in-hospital mortality were significantly higher in the DU-IE group. Redo valve procedures in DU-IE patients were associated with worse outcomes, compared with those receiving a first valve operation. CONCLUSIONS: Operations for DU-IE have increased sharply in the United States during the last several years, exhibiting substantial regional variability. DU-IE patients have unique clinical profiles, and worse risk-adjusted outcomes. This demonstrates the significant impact of the opioid epidemic on endocarditis surgeries and punctuates the urgent need for multidisciplinary regional and national efforts to reverse this trend.