Background <p>Terlipressin’s role as an adjunctive vasopressor in septic shock remains controversial. We aimed to evaluate the efficacy of terlipressin versus placebo as an additional vasopressor in refractory septic shock.</p> Methods <p>We conducted a single-center, prospective, double-blind, randomized controlled trial in a medical intensive care unit. Adult patients with septic shock requiring norepinephrine &gt; 0.2 mcg/kg/min or epinephrine were randomly assigned (1:1) to receive terlipressin or placebo. The primary outcome was the proportion of patients achieving mean arterial pressure ≥ 65 mmHg with total catecholamine equivalent dose below 0.2 mcg/kg/min at 6 h after randomization.</p> Results <p>A total of 130 patients were enrolled: 66 in the terlipressin group and 64 in the placebo group. Baseline characteristics were comparable. The median (interquartile range) baseline norepinephrine equivalent dose was 0.39 (0.29 − 0.73) mcg/kg/min for terlipressin versus 0.39 (0.27 − 0.62) mcg/kg/min for placebo. Pneumonia (57.6% vs 48.4%) and intra-abdominal infection (21.2% vs 23.4%) were the most common etiologies in the terlipressin and placebo arms, respectively. Significantly more patients met the primary outcome with terlipressin than with placebo (22.7% vs 9.4%; relative risk [RR] = 1.53, 95% confidence interval [CI] = 1.09–2.14; <i>P</i> = 0.039). The 28-day mortality was 60.6% in the terlipressin group versus 64.1% in the placebo group (RR = 0.93, 95% CI = 0.66–1.31; <i>P</i> = 0.68). Digital ischemia occurred in 28.8% versus 27.4% (<i>P</i> = 0.86).</p> Conclusions <p>Among patients with refractory septic shock, adjunctive terlipressin reduced the proportion of patients requiring high-dose catecholamines at 6 h, without significantly altering mortality or digital ischemia risk.</p> Trial registration <p>Clinicaltrials.gov (NCT 04339868). The registration date was April 7, 2020.</p>