Introduction: Infective endocarditis (IE) is a disease with high in-hospital and longer term mortality. Hypothesis: A validated risk model of prognostic variables may improve clinical risk stratification. Methods: Using a large, multinational, prospective registry of definite IE (International Collaboration on Endocarditis-Prospective Cohort Study, 2000-2006, n=4066), a model to predict 6-month survival was developed by Cox proportional hazard modeling with inverse probability weighting for surgery treatment and internally validated by bootstrapping method. This model was externally validated in an independent prospective registry (ICE-PLUS, 2008-2012, n=1582). Results: Six-month mortality was 964/4066 (23.7%) in ICE-PCS and 346/1582 (21.9%) in ICE-PLUS cohorts. Surgery during the index hospitalization was performed in 49.5% and 56.0% of the cohorts, respectively. In the derivation model, variables related to host factors (age, dialysis), IE characteristics (prosthetic or nosocomial IE, causative organism, left-sided valve vegetation), and IE complications (severe heart failure, stroke, paravalvular complication, and persistent bacteremia) were independently associated with 6-month mortality, and surgery was associated with a lower risk of mortality (Harrell’s C statistic=0.715). In the validation model, these variables had similar hazard ratios (Harrell’s C statistic=0.682), with a similar, independent benefit of surgery (HR=0.74 [95% CI, 0.62-0.89]). Both models differentiated quintiles of risk for 6-month mortality. A simplified risk model was developed by weight-adjustment of these variables. Conclusions: Six-month mortality after IE is approximately 25% and predicted by host factors, IE characteristics, and IE complications. Surgery during the index hospitalization is associated with lower mortality. A simplified risk model may be used to identify specific risk sub-groups in IE.