In patients with septic shock, does vasopressin, compared to norepinephrine, improve clinical outcomes when used as an adjunctive vasopressor therapy? The Vasopressin and Septic Shock Trial (VASST) investigated whether low-dose vasopressin, compared to norepinephrine, improves outcomes in patients with septic shock requiring vasopressor support to maintain mean arterial pressure (MAP). This multicenter, randomized controlled trial enrolled 778 patients and randomized them to receive blinded infusions of either vasopressin (0.01–0.03 U/min) or norepinephrine (5–15 μg/min) in addition to standard care, titrated to a target MAP of 65–75 mm Hg. If infusion with the study drug was unable to sustain the target MAP, open-label vasopressors were allowed. The primary outcome, 28-day mortality, showed no significant difference between the two groups overall. However, a subgroup analysis suggested a potential mortality benefit with vasopressin in patients with less severe septic shock (baseline norepinephrine requirement <15 μg/min), while no benefit was observed in patients with more severe shock. Secondary outcomes, including organ dysfunction scores, vasopressor-free days, and rates of adverse events such as arrhythmias, were similar between groups. The trial concluded that vasopressin is a safe adjunct to norepinephrine but does not improve overall mortality in septic shock, though it may offer benefits in less severe cases.