Infective endocarditis (IE) remains severe. Few predictors of prognosis have been identified. It is not known whether mortality of IE has decreased during recent decades. 559 definite cases of IE were collected in a prospective population-based survey in 1999 in France. In-hospital death rate was 17%. It was lower in operated patients (14.4% vs 19.3%), although not significantly so. In multivariate analysis, the following variables were independent and significant predictors of mortality: history of heart failure (odds ratio: 2.65), history of immunosuppression (OR: 3.34), insulin-requiring diabetes mellitus (OR: 7.82), left-sided IE (OR: 1.97), heart failure (OR: 2.19), septic shock (OR: 4.33), lower Glasgow coma scale score (OR: 4.09), cerebral haemorrhage (OR: 9.46), and higher C-reactive protein level (OR: 2.60). Adjusted mortality was significantly lower in 1999 than in 1991 (22%): OR: 0.64 (p = 0.03). Thus, in a large and unselected cohort of patients hospitalized for IE in 1999, in-hospital mortality rate was lower than in 1991. Multivariate analysis identified factors classically known as having an impact on mortality. However, other factors, such as age and responsibility of Staphylococcus aureus, were not retained in the model.