Background: Aortic valve infective endocarditis (AV-IE) and mitral valve infective endocarditis (MV-IE) are often grouped together as one entity: left-sided endocarditis. However, there are significant differences between the valves in terms of anatomy, physiology, pressure, and calcification tendency. This study aimed to compare AV-IE and MV-IE in terms of patient characteristics, pathogen profiles, postoperative outcomes, and predictors of mortality. Methods: We retrospectively analyzed data from 3899 patients operated on for isolated AV-IE or MV-IE in six German cardiac surgery centers between 1994 and 2018. Univariable and multivariable analyses were performed to analyze the risk factors for 30 day and 1 year mortality. A Log-rank test was used to test for differences in long-term mortality. Results: Patients with MV-IE were more likely to be female (41.1% vs. 20.3%.; p < 0.001). Vegetation was detected more frequently in the MV-IE group (66.6% vs. 57.1%; p < 0.001). Accordingly, the rates of cerebral embolic events (25.4% vs. 17.7%; p < 0.001) and stroke (28.2% vs. 19.3%; p < 0.001) were higher in the MV-IE group. Staphylococci had a higher prevalence in the MV-IE group (50.2% vs. 36.4%; p < 0.001). Patients with MV-IE had comparable 30 day mortality (16.7% vs. 14.6%; p = 0.095) but significantly higher 1 year mortality (35.3% vs. 29.0%; p < 0.001) than those with AV-IE. Kaplan–Meier survival analysis showed significantly lower long-term survival in patients with MV-IE (log-rank p < 0.001). Conclusions: Due to the relevant differences between MV-IE and AV-IE, it might be useful to provide individualized, valve-specific guideline recommendations rather than general recommendations for left-sided IE.