The aim of the study was to describe the epidemiological and clinical aspects of native valve infective endocarditis (IE) in a Tunisian high-volume tertiary care center and to identify the predictors of outcome. Demographic, clinical, laboratory, and echocardiographic characteristics were examined in 134 patients who fulfilled the modified Duke criteria for native valve IE between January 1997 and December 2006. Logistic regression analysis was used to identify prognostic factors for death. Mean age was 34.22 years. Diagnosis was definite in 93% of cases. Median time to diagnosis was 21 days. Rheumatic heart disease (RHD) was the predominant (45%) underlying heart condition. One or more vegetations were detected in more than 93% of cases. The median size of vegetation was >15 mm in 28% of cases. In 66 cases (49%), cultures remained negative. Serology was positive in 15 cases, and in 4 cases leaflet culture identified the agent. The infective agent was identified in 87 cases (65%), causative microorganisms were mainly Staphylococci (n = 30, including 6 coagulase-negative Staphylococcus), and Streptococci (n = 32). Overall mortality was 19%. On multivariate analysis, congestive heart failure (hazard ratio = 5.34, 95% confidence interval 1.67 to 17.15, p = 0.005) and large vegetations (>15 mm; hazard ratio = 5.78, 95% confidence interval 1.84 to 18.32, p = 0.002) were predictive of in-hospital mortality but not neurological complications or staphylococcus IE. In conclusion, IE remains a serious disease affecting a young population in Tunisia, with RHD as still the most common underlying heart disease, and it is associated with a high mortality.