Abstract The study objective was to derive and validate a clinical decision rule for obtaining blood cultures in Emergency Department (ED) patients with suspected infection. This was a prospective, observational cohort study of consecutive adult ED patients with blood cultures obtained. The study ran from February 1, 2000 through February 1, 2001. Patients were randomly assigned to derivation (2/3) or validation (1/3) sets. The outcome was “true bacteremia.” Features of the history, co-morbid illness, physical examination, and laboratory testing were used to create a clinical decision rule. Among 3901 patients, 3730 (96%) were enrolled with 305 (8.2%) episodes of true bacteremia. A decision rule was created with “major criteria” defined as: temperature > 39.5°C (103.0°F), indwelling vascular catheter, or clinical suspicion of endocarditis. “Minor criteria” were: temperature 38.3–39.4°C (101–102.9°F), age > 65 years, chills, vomiting, hypotension (systolic blood pressure < 90 mm Hg), neutrophil% > 80, white blood cell count > 18 k, bands > 5%, platelets < 150 k, and creatinine > 2.0. A blood culture is indicated by the rule if at least one major criterion or two minor criteria are present. Otherwise, patients are classified as “low risk” and cultures may be omitted. Only 4 (0.6%) low-risk patients in the derivation set and 3 (0.9%) low-risk patients in the validation set had positive cultures. The sensitivity was 98% (95% confidence interval CI 96–100%) (derivation) and 97% (95% CI 94–100%) (validation). We developed and validated a promising clinical decision rule for predicting bacteremia in patients with suspected infection.