Purpose: Both the blood glucose target range in critically ill adult patients and the optimal method to reach this target range remain a matter of debate. To test whether a Computer Decision Support System (CDSS) might improve the outcome of critically ill adult patients through facilitation of a tighter blood glucose control. Methods: We conducted a multicenter randomized trial in 34 French closed-format intensive care units in 19 university hospitals and 15 nonuniversity hospitals from October 2009 to June 2011. Adult patients who were expected to require treatment in the ICU at least 3 days were randomly assigned without blinding to undergo tight computerized glucose control with CDSS or conventional glucose control, with the respective blood glucose targets of 80 to 110 and < 180 mg per deciliter. The primary outcome was all-cause death within 90 days after ICU admission. Results: Of the 2,684 patients who underwent randomization, 1,351 were assigned to tight computerized glucose control and 1,333 to conventional glucose control. Data with regard to the primary outcome were available for 1,335 and 1,311 patients, respectively. A total of 431 (32.3%) patients in the tight computerized glucose control group and 447 (34.1%) in the conventional glucose control group died at day 90 (odds ratio for death in the tight computerized glucose control, 0.92; 95% CI, 0.78-1.78; p = 0.32). Severe hypoglycemia (< 40 mg/dL) was reported in 174 of 1,317 patients (13.2%) in the tight computerized glucose control group and 79 of 1,284 patients (6.2%) in the conventional glucose control group (p < 0.001). Conclusions: In critically ill patients, tight computerized glucose control with CDSS did not significantly change 90-day mortality and is associated with more frequent severe hypoglycemia in comparison with conventional glucose control performed without CDSS.