Compared with the conventional approach, which recommended only insulin therapy when blood glucose levels exceeded 12 mmol/liter, strict maintenance of blood glucose levels less than 6.1 mmol/liter with intensive insulin therapy has shown to reduce intensive care mortality, acute renal failure, critical illness polyneuropathy, and bloodstream infections in critically ill patients by about 40%. This study of 363 patients, requiring intensive care for more than 7 d and randomly assigned to either conventional or intensive insulin therapy, examines the effects of intensive insulin therapy on glucose and lipid homeostasis and their respective impact on the improved outcome. Intensive insulin therapy effectively normalized blood glucose levels within 24 h, both in survivors and nonsurvivors. Intensive insulin therapy also increased serum levels of low-density lipoprotein (P = 0.007) and high-density lipoprotein (P = 0.005), whereas it suppressed the elevated serum triglyceride concentrations (P < 0.0001). Multivariate logistic regression analysis, corrected for baseline univariate risk factors and the effect on inflammation, indicated that lipid rather than glucose control independently determined the beneficial effects of intensive insulin therapy on morbidity and mortality. In postmortem biopsies obtained from 74 patients who died in the intensive care unit, intensive insulin therapy increased mRNA levels of skeletal muscle glucose transporter 4 (P = 0.02) and hexokinase (P = 0.03), unlike those of hepatic glucokinase. In conclusion, our data suggest that intensive insulin therapy normalizes blood glucose levels through stimulation of peripheral glucose uptake and concomitantly partially restores the abnormalities in the serum lipid profile, which may have contributed significantly to the improved outcome of protracted critical illness.