Background: The use of low-dose vasopressin as an adjunctive vasopressor in septic shock is common, but its effect on mortality is unknown. Objective: To determine whether a low-dose vasopressin infusion reduces mortality in septic shock when added to an infusion of norepinephrine. Design and Setting: Multicentre, multiple-blinded, randomized controlled trial conducted in three countries from July, 2001 to April, 2006. Patients: Inclusion criteria were patients C17 years of age with septic shock requiring C5 ug min of norepinephrine (or equivalent) for C6 h, or requiring C15 ug min of norepinephrine (or equivalent) for C3 h, despite having received C500 ml of normal saline. Study enrolment was only permitted within 24 h of meeting inclusion criteria. Exclusion criteria included previous use of vasopressin, acute myocardial infarction, New York Heart Association class III or IV congestive heart failure, acute mesenteric ischemia, severe traumatic brain injury, hyponatremia \130 mmol l, Raynaud’s phenomenon, systemic sclerosis, vasospastic diathesis, pregnancy, an irreversible condition with an estimated six-month mortality C50%, anticipated death within 12 hr, or the decision not to proceed with aggressive care. Intervention: Study patients were randomized to a blinded infusion of vasopressin (started at 0.01 U min and titrated to 0.03 U min over 40 min) or norepinephrine (started at 5 ug min and titrated to 15 ug min over 40 min). Additional open-label vasopressors (excluding vasopressin) were administered as necessary to maintain a target mean arterial pressure (MAP) of 65–75 mmHg. The study drug could be tapered after the target MAP had been maintained for[8 h without open-label vasopressors. Measurements: The primary outcome was 28-day mortality. Secondary outcomes included 90-day mortality, rates of adverse events, and markers of clinical illness (e.g., organ dysfunction scores, need for vasopressors, mechanical ventilation, and renal replacement therapy). A priori subgroup analysis was performed on patients with less severe vs more severe septic shock (defined by the need for 5–14 ug min vs. C15 ug min of norepinephrine, respectively, at the time of study enrolment). Main results: Seven hundred seventy-eight patients were included in the final analysis. There were no statistically significant differences between the vasopressin and the norepinephrine groups in terms of 28-day mortality (35.4 vs. 39.3%, respectively, P = 0.26), 90-day mortality (43.9 vs. 49.6%, respectively, P = 0.11), rates of organ dysfunction, or overall rates of adverse events. Patients with less severe septic shock who were randomized to vasopressin had a trend towards decreased 28-day mortality (26.5 vs. 35.7%, respectively, P = 0.05) and 90-day mortality (35.8 vs. 46.1%, respectively, P = 0.04). Conclusions: An adjunctive vasopressin infusion does not reduce overall mortality in septic shock, but may benefit patients with less severe septic shock. R. Keyes, MD (&) P. G. Brindley, MD University of Alberta, Edmonton, Canada e-mail: rkeyes@ualberta.ca