IGF binding protein-1 (IGFBP-1), an important regulator of IGF bioavailability, has been shown to correlate with mortality in critically ill patients. In the liver, IGFBP-1 is transcriptionally repressed by insulin, and it is therefore a potential marker of hepatic insulin sensitivity. We have recently shown that, compared with conventional treatment, maintenance of normoglycemia with intensive insulin therapy decreased morbidity and mortality of continuously fed critically ill patients. This study compares the effect of conventional and intensive insulin therapy on IGFBP-1 and assesses its predictive value for mortality. In 363 patients who were dependent on intensive care for more than 7 d and were randomly assigned to either conventional or intensive insulin therapy, serum IGFBP-1 levels were measured on admission, on d 1, 8, 15, 22, and 29, and on the day of intensive care unit discharge or death. In addition, IGFBP-1 and phosphoenolpyruvate carboxykinase mRNA levels were measured by real-time RT-PCR in postmortem liver biopsies obtained from 74 patients who died in the intensive care unit. Although intensive insulin treatment lowered glycemia, it had no effect on IGFBP-1 serum levels. Instead, serum IGFBP-1 concentration was significantly higher in patients who ultimately died, and it differentiated nonsurvivors from survivors 3 wk before death. The predictive value of serum IGFBP-1 for mortality was similar to that of the APACHE-II score. Like circulating IGFBP-1, hepatic mRNA levels of IGFBP-1 and the similarly insulin-regulated gene, phosphoenolpyruvate carboxykinase, were not significantly different between conventional and intensive insulin therapy groups. These data suggest that hepatic insulin resistance in prolonged critically ill patients, reflected by high serum IGFBP-1 levels, is not overcome by intensive insulin therapy, and that this may affect patient outcome.