Abstract To investigate the clinical outcomes of patients with septic shock related to community-onset monomicrobial Enterobacteriaceae (CoME) bacteremia as categorized by the strategy of antimicrobial therapy, a retrospective and observational study was conducted. Clinical information on the patients was obtained from medical records. Antibiotic regimens were ranked according to their activity spectrum against Enterobacteriaceae (category IV, highest; I, lowest). De-escalation was defined as a switch to a category with a narrower spectrum of coverage within 5 days after the bacteremic onset. Of the 189 eligible patients, 86 (45.5%) patients received de-escalation antibiotic therapy, and most (48, 55.8%) of the patients were empirically treated first with a category IV antibiotic. In a multivariate analysis for 28-day mortality, of several independent predictors, the de-escalation strategy was protective (odds ratio, 0.37; P = 0.04). In conclusion, for patients with CoME bacteremia and available susceptibility data, de-escalation of antimicrobial therapy was beneficial for improving clinical outcome.