Introduction: Despite improvements in guidelines, the prognosis of infective endocarditis (IE) remains poor. To guide future development of management strategies, we aim to fill the knowledge gap and identify the evolving factors contributing to mortality. Methods: All patients diagnosed with IE from 2002 to 2019 were included from a well-validated territory-wide database in Hong Kong. Information including demographics, comorbidities and Charlson Comorbidity Index (CCI), microbiological culture and sensitivity tests, and surgical interventions were retrieved. The primary outcome was 1-year all-cause mortality. Using population attributable fraction (PAF) analysis, we quantified the relative contribution of each factor to the risk of death. The temporal trends in risk attributable to each factor was also evaluated using linear regression. Results: Of a total of 5139 patients (mean age 60 years, 37% female), 1642 (32%) died in one year. Age ≥ 60 years and CCI ≥ 1 were the most detrimental contributors to death, with PAF of 19.2% (14.5 to 23.9) and 14.6% (10.6 to 18.5), respectively (Figure). Concurrently, a hospital-acquired nature and severe renal disease also increased the risk of death, with PAF of 1.8% (0.2 to 3.4) and 1.8% (0.5 to 3.2), respectively. Methicillin-resistant Staphylococcus Aureus (MRSA) endocarditis was the most important microbiological factor penalizing survival (PAF 3.4% [2.5 to 4.3]). Surgical intervention was protective, with PAF of -7.9% (-9.5 to -6.4), and the PAF of surgery significantly increased over time (P < 0.001). Discussion: Age, comorbidities, impaired renal function, hospital-acquired IE and MRSA were the most detrimental contributors to adverse outcomes; the mounting coexistence represents a major challenge to diagnosis, treatment, and prognosis. Surgical intervention offered significant and increasing survival benefits, and a surgery-centered approach in management of endocarditis should be promoted.