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Angiotensin II and its postreceptor signaling are crucial in regulating vasomotor tone. The objective of this study was to test the hypothesis that single nucleotide polymorphisms in angiotensin II pathway genes alter outcome of septic shock.Genetic association study and in vitro experiment.Intensive care units at academic teaching centers.Derivation and validation septic shock cohorts (n = 589 and n = 616, respectively) and a coronary artery bypass surgery cohort (n = 551).Patients with septic shock in the derivation cohort were genotyped for tag single nucleotide polymorphisms: angiotensin-converting enzyme (six single nucleotide polymorphisms), angiotensin II receptor type 1 (five single nucleotide polymorphisms), and angiotensin II type 1 receptor-associated protein (three single nucleotide polymorphisms), which is a negative regulator of angiotensin II receptor type 1. Patients in the septic shock replication cohort and the coronary artery bypass graft cohort were genotyped for the angiotensin II type 1 receptor-associated protein rs11121816.The primary outcome variable was 28-day mortality. Secondary outcome variables were blood pressure and heart rate. Angiotensin II type 1 receptor-associated protein messenger RNA expression was measured in genotyped lymphoblastoid cells in vitro. Patients with septic shock patients the GG genotype of angiotensin II type 1 receptor-associated protein rs11121816 had increased 28-day mortality in the derivation cohort (54.8% vs. 41.4%; adjusted hazard ratio, 1.46; 95% confidence interval, 1.09–1.93; p = .010 [all ethnicities]; p = .050 [white]) and in the replication cohort (43.8% vs. 32.3%; hazard ratio, 1.42; 95% confidence interval, 1.03–1.98; p = .035 [all ethnicities]; p = .037 [white]). Patients having the GG genotype had decreased mean arterial pressure (98.3% of other genotype, p = .058 [derivation cohort]; 97.7%, p = .00060 [replication cohort]) and increased heart rate (104.1%, p = .023 [derivation cohort], 102.9%, p = nonsignificant [replication cohort]). GG genotype patients undergoing coronary artery bypass grafting had decreased postoperative mean arterial pressure and increased postoperative heart rate (p < .05). GG genotype lymphoblastoid cells had 2.0-fold higher angiotensin II type 1 receptor-associated protein messenger RNA expression (p < .05).For angiotensin II type 1 receptor-associated protein, the negative regulator of angiotensin II receptor type 1, the GG genotype of rs11121816 was associated with increased angiotensin II type 1 receptor-associated protein expression, decreased blood pressure, and increased heart rate as well as increased 28-day mortality in septic shock.