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Objective: To determine the annual incidence of prosthetic valve endocarditis (PVE) and to evaluate its current classification based on the epidemiological distribution of agents identified and their sensitivity profiles. Methods: Consecutive cases of PVE occurring within the first year of valve surgery during the period 1997–2014 were included in this prospective cohort study. Incidence, demographic, clinical, microbiological, and in-hospital mortality data of these PVE patients were recorded. Results: One hundred and seventy-two cases of PVE were included, and the global annual incidence of PVE was 1.7%. Most PVE cases occurred within 120 days after surgery (76.7%). After this period, there was a reduction in resistant microorganisms (64.4% vs. 32.3%, respectively; p = 0.007) and an increase in the incidence of Streptococcus spp (1.9% vs. 23.5%; p = 0.007). A literature review revealed 646 cases of PVE with an identified etiology, of which 264 (41%) were caused by coagulase-negative staphylococci and 43 (7%) by Streptococcus spp. This is in agreement with the current study findings. Conclusions: Most PVE cases occurred within 120 days after valve surgery, and the same etiological agents were identified in this period. The current cut-off level of 365 days for the classification of early-onset PVE should be revisited.