Background: Drawing blood cultures in the emergency room (ER) is essential for detecting bloodstream infections (BSIs). Although a practice of drawing blood culture usually indicates a presence of severe infection requiring hospitalization, some patients may nonetheless be safely discharged from the ER. Previous studies demonstrated that patients with a positive blood culture after ER discharge had favorable clinical outcomes. Moreover, given the increasing incidence of febrile illnesses, especially in the era of COVID-19, the shortage of inpatient hospital beds may lend further justification to this practice. We investigated the prevalence, outcomes, and factors associated with patient discharge from the ER after blood collection. Method: The present, nested, case–control study comparing patients initially discharged from the ER with those directly admitted to the study institution was conducted at a 790-bed tertiary-care medical center in Tokyo, Japan. The ratio of the respective patients was 1:3. Factors associated with ER discharge after a blood-culture collection were identified using multivariate logistic regression analysis. Results: From January 2014 through December 2020, 153,432 patients visited the ER. Blood cultures were obtained for 19,010 patients; 2,575 (13.5%) of these had a true BSI, and of the latter, 142 (5.5%) were initially discharged from the ER. During 2020, the proportion of patients with ER discharge increased 1.7 times over previous years. There was no significant difference in 28-day mortality between the groups (2.1% vs 4.5%; P = .31). On multivariate logistic regression analysis, factors significantly associated with the decision to discharge after blood culture collection were the absence of hypotension (aOR], 14,92; 95% CI, 3.38–65.93), lack of altered mental status (aOR, 8.44; 95% CI, 3.28–21.71) at ER presentation, unknown diagnosis at ER discharge (aOR, 3.75; 95% CI, 1.97–7.16), high level C-reactive protein (aOR, 0.91; 95% CI, 0.87–0.94), and a diagnosis of intra-abdominal or hepatobiliary infection (aOR, 0.11; 95% CI, 0.04–0.29). Conclusions: ER discharge after drawing blood for a culture was more frequently seen in the current COVID-19 era and was deemed acceptable under certain circumstances, such as patients with no systemic illnesses or specific diagnosis who may be managed safely without compromising clinical outcomes.