ABSTRACT: INTRODUCTION: Critically ill patients requiring intensive care uniformly develop insulin resistance. This is most pronounced in patients with sepsis. Recently, several hormones secreted by adipose tissue have been identified to be involved in overall insulin sensitivity in metabolic syndrome-related conditions. However, little is known about these adipokines in critical illness. METHODS: We studied circulating levels of the adipokines adiponectin, retinol-binding protein 4 (RBP4), and leptin during critical illness, and the impact of intensive insulin therapy, a therapy shown to affect insulin sensitivity, in serum samples from prolonged critically ill patients with a respiratory critical illness (n = 318). For comparison, we studied healthy subjects (n = 22) and acutely stressed patients (n = 22). RESULTS: During acute critical illness, circulating levels of adiponectin, RBP4, and leptin were low. Patients with sepsis had lower levels of leptin and RBP4 than did nonseptic patients. When critical illness was sustained, adipokine levels returned to normal reference values. Insulin therapy enhanced adiponectin, blunted the rise of RBP4, and did not alter leptin levels. CONCLUSIONS: Acute critical illness is associated with immediate, but transiently low serum adipokine levels. Adiponectin and RBP4 are associated with altered insulin resistance in critical illness.