Background Infective endocarditis (IE) could be suspected in any febrile patients admitted to the emergency department (ED). This study was aimed at assessing clinical criteria predictive of IE and identifying and prospectively validating a sensible and easy‐to‐use clinical prediction score for the diagnosis of IE in the ED. Methods and Results We conducted a retrospective observational study, enrolling consecutive patients with fever admitted to the ED between January 2015 and December 2019 and subsequently hospitalized. Several clinical and anamnestic standardized variables were collected and evaluated for the association with IE diagnosis. We derived a multivariate prediction model by logistic regression analysis. The identified predictors were assigned a score point value to obtain the Clinical Rule for Infective Endocarditis in the Emergency Department (CREED) score. To validate the CREED score we conducted a prospective observational study between January 2020 and December 2021, enrolling consecutive febrile patients hospitalized after the ED visit, and evaluating the association between the CREED score values and the IE diagnosis. A total of 15 689 patients (median age, 71 [56–81] years; 54.1% men) were enrolled in the retrospective cohort, and IE was diagnosed in 267 (1.7%). The CREED score included 12 variables: male sex, anemia, dialysis, pacemaker, recent hospitalization, recent stroke, chest pain, specific infective diagnosis, valvular heart disease, valvular prosthesis, previous endocarditis, and clinical signs of suspect endocarditis. The CREED score identified 4 risk groups for IE diagnosis, with an area under the receiver operating characteristic curve of 0.874 (0.849–0.899). The prospective cohort included 13 163 patients, with 130 (1.0%) IE diagnoses. The CREED score had an area under the receiver operating characteristic curve of 0.881 (0.848–0.913) in the validation cohort, not significantly different from the one calculated in the retrospective cohort ( P =0.578). Conclusions In this study, we propose and prospectively validate the CREED score, a clinical prediction rule for the diagnosis of IE in patients with fever admitted to the ED. Our data reflect the difficulty of creating a meaningful tool able to identify patients with IE among this general and heterogeneous population because of the complexity of the disease and its low prevalence in the ED setting.