Prosthetic valve endocarditis is associated with worse outcomes compared with native valve endocarditis. Our aim was to evaluate the impact of native valve endocarditis versus prosthetic valve endocarditis on postoperative outcomes and long-term survival and to identify preoperative risk factors in a large cohort of 4300 patients with infective endocarditis. This retrospective cohort study was conducted in 5 German Cardiac Surgery Centers: the Clinical Multicenter Project of Analysis of Infective Endocarditis in Germany. Data of 4300 patients undergoing valve surgery for native valve endocarditis and prosthetic valve endocarditis were retrospectively analyzed. Univariable and multivariable analyses were used for risk stratification, Kaplan-Meier analysis for long-term survival. In addition, we performed Cox proportional hazards regression with multivariable adjustment. Between 1994 and 2016, 3143 patients (73.1%) underwent surgery for native valve endocarditis and 1157 patients (26.9%) underwent surgery for prosthetic valve endocarditis. Patients with prosthetic valve endocarditis were older (69 [60-75] vs 63 [52-72] years; P < .001) and had more comorbidities, such as hypertension (55% vs 46%; P < .001), diabetes (28% vs 25%; P = .020), coronary artery disease (32% vs 23%; P < .001), and preoperative acute kidney injury (41% vs 32%; P < .001). Kaplan-Meier analysis revealed significantly decreased long-term survival of patients undergoing surgery for prosthetic valve endocarditis compared with native valve endocarditis (P < .001). However, after multivariable adjustment, there was no significant difference in long-term survival between patients undergoing cardiac surgery with prosthetic valve endocarditis compared with native valve endocarditis. After adjusting for preoperative comorbidities, long-term survival for prosthetic valve endocarditis and native valve endocarditis is comparable. Thus, our large cohort study provides evidence that prosthetic valve endocarditis alone should not be a contraindication for redo operations. Copyright © 2019 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.