© 2019 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley. Background: There has been an increase in the prevalence of drug abuse (DA) in the national opioid epidemic. With increasing DA, there is an increased risk of infective endocarditis (IE). There are limited recent data evaluating national trends on the incidence and geographical distribution of DA-IE. We aim to investigate those numbers as well as the determinants of outcome in this patient population. Methods and Results: Hospitalized patients with a primary or secondary diagnosis of IE based on the International Classification of Diseases, Ninth and Tenth Revisions (ICD-9, ICD-10) were included. We described the national and geographical trends in DA-IE. We also compared DA-IE patients’ characteristics and outcomes to those with IE, but without associated drug abuse (non-DA-IE) using Poisson regression models. Incidence of DA-IE has nearly doubled between 2002 and 2016 All US regions were affected, and the Midwest had the highest increase in DA-IE hospitalizations (annual percent change=4.9%). Patients with DA-IE were younger, more commonly white males, poorer, had fewer comorbidities, and were more likely to have human immunodeficiency virus, hepatitis C, concomitant alcohol abuse, and liver disease. Their length of stay was longer (9 versus 7 days; P<0.001) and were more likely to undergo cardiac surgery (7.8% versus 6.2%; P<0.001), but their inpatient mortality was lower (6.4% versus 9.1%; P<0.001). Conclusions: DA-IE is rising at an alarming rate in the United States. All regions of the United States are affected, with the Midwest having the highest increase in rate. Young-adult, poor, white males were the most affected.