Although etomidate is a preferred anesthetic agent for rapid sequence intubation (RSI) in critical illness, as an inhibitor of cortisol synthesis (11β-hydroxylase), it may be associated with adrenal dysfunction. The objectives are to review the effects of etomidate versus comparator anesthetics in critical illness for: primary outcome of mortality and secondary outcome of adrenal insufficiency (AI). Studies were extracted using MEDLINE and SCOPUS, regardless of language, between 1983 and 2010 using the keywords etomidate, intensive care units (ICU), critical illness, intensive care, glucocorticoids, and adrenal insufficiency. Studies of single dose etomidate versus comparator anesthetics with outcomes of adrenal function and/or mortality were included. All reviewers performed electronic data searches. One reviewer extracted data, which were checked by the other reviewers. Authors of trials were contacted for supplemental data. Primary outcome was 28-day mortality. AI was defined per article. Two hundred sixty-three articles were screened, and 21 articles (19 independent data sets) were evaluated. Meta-analysis comparing etomidate versus non-etomidate anesthesia demonstrated an increased risk ratio (RR) for AI of 1.64 (range 1.52–1.77; 14 studies, 2,854 patients, P < 0.0001, I 2 = 88%) and an increased RR for mortality of 1.19 (1.10–1.30; 14 studies, 3,516 patients, P < 0.0001, I 2 = 64%). Significance of re-analysis for mortality within the subset of sepsis was maintained [RR 1.22 (1.11–1.35), 7 studies, n = 1,767, I 2 = 74%, P < 0.0001], but not for trials without sepsis [RR = 1.15 (0.97–1.35), 7 studies, n = 1,749, I 2 = 53%, P = 0.10]. There is an increased rate of AI and mortality in critically ill patients who received etomidate.