OBJECTIVE To describe the relationships among glycemic control, diabetes mellitus (DM) status, and mortality in critically ill patients from intensive care unit (ICU) admission to hospital discharge. PATIENTS AND METHODS This is a retrospective investigation of 6387 ICU patients with 5 or more blood glucose (BG) tests and 4462 ICU survivors admitted to 2 academic medical centers from July 1, 2010, through December 31, 2014. We studied the relationships among mean BG level, hypoglycemia (BG level <70 mg/dL [to convert to mmol/L, multiply by 0.0555]), high glucose variability (coefficient of variation ≥20%), DM status, and mortality. RESULTS The ICU mortality for patients without DM with ICU mean BG levels of 80 to less than 110, 110 to less than 140, 140 to less than 180, and at least 180 mg/dL was 4.50%, 7.30%, 12.16%, and 32.82%, respectively. Floor mortality for patients without DM with these BG ranges was 2.74%, 2.64%, 7.88%, and 5.66%, respectively. The ICU and floor mean BG levels of 80 to less than 110 and 110 to less than 140 mg/dL were independently associated with reduced ICU and floor mortality compared with mean BG levels of 140 to less than 180 mg/dL in patients without DM (odds ratio [OR] [95% CI]: 0.43 (0.28-0.66), 0.62 (0.45-0.85), 0.41 (0.23-0.75), and 0.40 (0.25-0.63), respectively) but not in patients with DM. Both ICU and floor hypoglycemia and increased glucose variability were strongly associated with ICU and floor mortality in patients without DM, and less so in those with DM. The independent association of dysglycemia occurring in either setting with mortality was cumulative in patients without DM. CONCLUSION These findings support the importance of glucose control across the entire trajectory of hospitalization in critically ill patients and suggest that the BG target of 140 to less than 180 mg/dL is not appropriate for patients without DM. The optimal BG target for patients with DM remains uncertain.