The aim of our study was to determine whether pre-emptive statin therapy was associated with improved outcome of infective endocarditis (IE). We conducted a nationwide, population-based, propensity score-matched cohort study with the Taiwan's National Health Insurance Research Database. All patients with IE between January 2000 and December 2010 were enrolled. The primary outcome was in-hospital mortality. The secondary outcome included all-cause mortality within the first 3 months, 6 months, and one year after the diagnosis of IE. Among 13,584 patients with IE, we applied propensity score-matching on a 1:4 ratio, in which 370 statin users were matched to 1,480 statin non-users. Compared with statin non-users, statin users had a significantly lower risk of in-hospital mortality (adjusted hazard ratio [aHR] 0.65, 95% confidence interval [CI], 0.49-0.86). The reduction in mortality from IE remained significant for follow-up 3 months (aHR 0.68, 95% CI, 0.53-0.88), 6 months (aHR 0.73, 95% CI, 0.58-0.91), and 12 months (aHR 0.68, 95% CI, 0.55-0.84). Statin therapy was associated with a reduced risk of ICU admission rates, shock events, the need for mechanical ventilation, but not significantly with the need for heart valvular replacement surgery. In conclusion, our study found that statin therapy is associated with a reduced risk of in-hospital and subsequent mortality of IE.