Background and Objectives. In 2002, French guidelines regarding antibiotic prophylaxis for infective endocarditis (IE) were revised, significantly narrowing its indications. The objective is to assess whether these changes were followed by alterations in the incidence and clinical presentation of IE. Methods. Three population-based studies, conducted across several French regions with a total population of 11 million and prospectively including all patients treated for IE, were carried out in 1991, 1999, and 2008. Age- and sex-standardized incidence rates were compared. Results. 993 cases of IE were analyzed (323 in 1991, 331 in 1999, and 339 in 2008). The incidence remained stable over time, with 35 (95% CI: [31–39]), 33 [30–37], and 32 [28–35] cases per million inhabitants in 1991, 1999, and 2008, respectively. The proportion of oral streptococci did not increase in the general population or in the population without prior valvular disease. The increase in the incidence of Staphylococcus aureus endocarditis (5.2 [3.9–6.8], 6.8 [5.3–8.6], and 8.2 [6.6–10.2]) is not statistically significant in the general population (p=0.228) but becomes so for the subgroup of patients without known valvular disease (1.6 [0.9–2.7], 3.7 [2.6–5.1], and 4.1 [3.0–5.6]; p=0.012) in 1991, 1999, and 2008, respectively. Conclusions. The narrowing of recommendations for IE prophylaxis was not accompanied by an increase in dental-related IE. However, efforts should be made to prevent S. aureus bacteremia in all patients, including those without pre-existing valvular disease, to reduce the incidence of IE. (R.A.)