Background The incidence and 30-day readmission rates of patients with infective endocarditis (IE) are not fully determined. We used the United States Nationwide Readmission Database (NRD) to assess national trends and predictors of 30-day readmission. Methods We queried the NRD from 2010 to 2014 and identified patients with index hospitalizations primarily for IE. Univariate and multivariate logistic regression analyses were conducted to identify predictors of 30-day readmission. Results A total of 48,500 patients (mean age 58 ± 19 years; 38% women; 6.4% died during index hospitalization) were admitted for IE. There was an annual decrease in hospitalization rates by 1.5%. With an exception for 2014, subsequent 30-day readmission rates remained relatively unchanged. All-cause 30-day readmission occurred in 25.4% of patients, 21.8% of which were due to acute or subacute bacterial endocarditis. Leaving against medical advice (odds ratio (OR): 3.46, 95% CI: 3.12 - 3.84; P <0.001), history of drug abuse and a cardiac implantable electronic device in situ (OR: 2.17, 95% CI: 1.53 - 3.08; P <0.001), fungal IE (OR: 1.5, 95% CI: 1.28 - 1.76; P < 0.001), and uninsured patients (OR: 1.39, 95% CI: 1.12 - 1.74, P <0.001) were the strongest independent predictors of 30-day readmission. Readmission cost ($58 million annually) accounted for 14% of the total hospitalization cost. Conclusions The annual incidence of IE in the US decreased slightly from 2010 to 2014, but the 30-day readmission rates remained relatively unchanged. Addressing modifiable predictors of readmission may reduce the financial burden of IE on health care.