ABSTRACT: : Adiponectin, an anti-inflammatory cytokine produced by adipose tissue, has been shown to modulate survival in animal models of critical illness. We examined the association between plasma adiponectin and clinical outcomes in critically ill patients with acute respiratory failure.: Secondary analysis of a single-center, randomized controlled trial.: Medical intensive care unit of a university-based, tertiary medical center.: One hundred seventy-five subjects with acute respiratory failure enrolled in randomized, controlled pilot trial of Early versus Delayed Enternal Nutrition (EDEN pilot study).: None.: Adiponectin measured within 48 hrs of respiratory failure (Apn1) was inversely correlated with body mass index (r=-0.25, p=.007) and was higher in females (median, 12.6 ?g/mL; interquartile range, 7.6-17.1) than males (9.45 ?g/mL; 6.2-14.2; p=.02). Adiponectin increased at day 6 (Apn1: 11.4 ?g/mL [6.6-15.3] vs. Apn6: 14.1 ?g/mL [10.3-18.6], p<.001). This increase was significant only in survivors (? adiponectin in survivors: 3.9±6 ?g/mL, n=80, p<.001 vs. ? in nonsurvivors: 1.69±4.6 ?g/mL, n=14, p=.19). Higher Apn1 was significantly associated with 28-day mortality (odds ratio 1.59 per 5-?g/mL increase; 95% confidence interval 1.15-2.21; p=.006). No measured demographic, clinical, or cytokine covariates, including interleukin-6, interleukin-8, interleukin-10, interleukin-1?, interleukin-12, tumor necrosis factor-?, and interferon-?, were confounders or effect modifiers of this association between adiponectin and mortality.: Independent of measured covariates, increased plasma adiponectin levels measured within 48 hrs of respiratory failure are associated with mortality. This finding suggests that factors derived from adipose tissue play a role in modulating the response to critical illness.