OBJECTIVES: Previous trials suggest that vasopressin may improve outcomes in patients with vasodilatory shock. The aim of this study was to evaluate whether vasopressin could be superior to norepinephrine to improve outcomes in cancer patients with septic shock. DESIGN: Single-center, randomized, double-blind clinical trial, and meta-analysis of randomized trials. SETTING: ICU of a tertiary care hospital. PATIENTS: Two-hundred fifty patients 18 years old or older with cancer and septic shock. INTERVENTIONS: Patients were assigned to either vasopressin or norepinephrine as first-line vasopressor therapy. An updated meta-analysis was also conducted including randomized trials published until October 2018. MEASUREMENTS AND MAIN RESULTS: The primary outcome was all-cause mortality at 28 days after randomization. Prespecified secondary outcomes included 90-days all-cause mortality rate; number of days alive and free of advanced organ support at day 28; and Sequential Organ Failure Assessment score 24 hours and 96 hours after randomization. We also measure the prevalence of adverse effects in 28 days. A total of 250 patients were randomized. The primary outcome was observed in 71 patients (56.8%) in the vasopressin group and 66 patients (52.8%) in the norepinephrine group (p = 0.52). There were no significant differences in 90-day mortality (90 patients [72.0%] and 94 patients [75.2%], respectively; p = 0.56), number of days alive and free of advanced organ support, adverse events, or Sequential Organ Failure Assessment score. CONCLUSIONS: In cancer patients with septic shock, vasopressin as first-line vasopressor therapy was not superior to norepinephrine in reducing 28-day mortality rate.