Whether infection in more than 1 valve worsens the prognosis for endocarditis remains untested. We conducted the current study to determine the profile of multiple-valve endocarditis, compare multiple-valve endocarditis with single-valve endocarditis, and determine predictors of outcome. We conducted a prospective and observational study including 680 episodes of infective endocarditis consecutively diagnosed at 3 tertiary centers. Multiple valve involvement was present in 115 episodes (17%), and single valve involvement in 530 (78%). In the remaining 35 cases, valvular involvement could not be documented. Mean age of patients with multiple valve endocarditis was 58 years. Clinical complications were frequent (heart failure 65%, renal failure 44%, systemic embolisms 24%). The microorganism most frequently isolated was Staphylococcus aureus (22%).Factors predictive of in-hospital mortality in the univariate analysis were septic shock, prosthetic endocarditis, heart failure, and persistent infection. In the multivariate analysis, we detected heart failure (odds ratios [OR], 4.7; 95% confidence interval [CI], 1.6-13.8) and persistent infection (OR, 4.3; 95% CI, 1.7-10.8) as predictors of in-hospital mortality. Compared to single-valve endocarditis, multiple-valve disease was associated more frequently with heart failure (65% vs. 50%, p = 0.03), perivalvular complications (41% vs. 21%, p < 0.001), and heart surgery (70% vs. 54%, p = 0.002). Despite these differences, in-hospital mortality was similar (28% vs. 30%, p = 0.647). In conclusion, multiple-valve endocarditis has a poor clinical course. Mortality is similar to that of single-valve endocarditis, probably in relation with aggressive therapy including surgery in many patients. Heart failure and persistent infection are independent predictors of death.