Historically, β-blockers have been considered to be relatively contraindicated for septic shock because they may cause cardiac suppression. On the other hand, there is an increasing interest in the use of β-blockers for treating septic patients with persistent tachycardia despite initial resuscitation.Do ultra-short-acting β-blockers such as esmolol and landiolol improve mortality in septic patients with persistent tachycardia despite initial resuscitation?This was a systematic review and meta-analysis. We searched MEDLINE, Cochrane Central Register of Controlled Trials, and Embase for RCTs that compared the mortality of patients with sepsis and septic shock treated with esmolol or landiolol. We updated our search on April 20, 2020. Two independent reviewers assessed whether titles and abstracts met the following eligibility criteria: (1) RCT, (2) patients with sepsis and septic shock aged ≥18 years, and (3) treatment with either esmolol/landiolol or placebo/no interventions. Two authors independently extracted selected patient and study characteristics and outcomes. The results of all analyses are presented using random-effect models.Seven RCTs with a pooled sample size of 613 patients were included. Of these, six RCTs with 572 patients reported 28-day mortality. Esmolol or landiolol use in patients with sepsis and septic shock was significantly associated with lower 28-day mortality (risk ratio, 0.68; 95% CI, 0.54-0.85; P < .001). Unimportant heterogeneity was observed (I2 = 31%). The absolute risk reduction and number of patients to be treated to prevent one death were 18.2% and 5.5, respectively.The use of ultra-short-acting β-blockers such as esmolol and landiolol in septic patients with persistent tachycardia despite initial resuscitation was associated with significantly lower 28-day mortality.UMIN000040174 (April 20, 2020).