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The role of the renin-angiotensin-aldosterone axis in vasoplegia after cardiac surgery remains unclear. We tested the hypothesis that, compared with norepinephrine, infusion of angiotensin II titrated to achieve similar mean arterial pressure (MAP) would suppress plasma renin concentration (PRC) while maintaining aldosterone levels. In a double-blind, randomised controlled trial, subjects received either an infusion of angiotensin II or norepinephrine to maintain MAP 70–80 mm Hg from induction of anaesthesia. We compared PRC, aldosterone, dipeptidyl peptidase-3, and angiotensin-converting enzyme 2 activity between treatment groups, before surgery, on ICU admission, and 24 h after surgery. In 60 patients (11.7% female; mean age 68 yr [11 yr]), norepinephrine increased median PRC at ICU admission (median difference [MD] 46 [inter-quartile range, IQR, 3–88] μU ml−1; P <0.001) but angiotensin II did not (MD −3 [IQR −62 to 35] μU ml−1; P =0.36). Aldosterone levels increased with both. The aldosterone:PRC ratio did not change with norepinephrine (MD −0.01 [IQR −0.14 to 0.03] μU ml−1 per ng dl−1, P =0.76) but increased with angiotensin II (MD 0.05 [IQR 0.004–0.26] μU ml−1 per ng dl−1, P <0.001). The upper quartile of PRC before surgery was associated with higher vasopressor requirements when norepinephrine was used to maintain MAP, but not angiotensin II. Dipeptidyl peptidase-3 levels and angiotensin-converting enzyme 2 activities were similar at all time points. Angiotensin II suppressed renin release while maintaining aldosterone levels compared with norepinephrine. Higher plasma renin concentration before surgery was associated with greater vasopressor requirement for norepinephrine, but not angiotensin II. Australian and New Zealand Clinical Trials Registry—ACTRN12621000195853 23/02/2021. [ABSTRACT FROM AUTHOR]