OBJECTIVE To test the hypothesis that the prevalence of hyperhomocysteinemia is increased in critically ill patients and correlates with disease severity and mortality in these patients. DESIGN A prospective study. SETTING Three medical intensive care units at the University of vienna Medical School serving both medical and surgical patients. PATIENTS All consecutive admissions (n = 56) during a period of 4 wks. A total of 112 age- and gender-matched healthy individuals constituted the control group. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS Blood samples were drawn within 24 hrs after admission for analysis of total homocysteine (tHcy), folate, vitamin B6 levels, and vitamin B12 levels as well as to identify the 677C-->T polymorphism in the gene coding for the enzyme 5,10-methylenetetrahydrofolate reductase. Acute Physiology and Chronic Health Evaluation III scores at admission and 24 hrs after admission as well as 30-day survival were documented in all patients. Hyperhomocysteinemia was more prevalent in critically ill patients (16.1%; 95% confidence interval, 7.6% to 28.3%) compared with age- and gender-matched healthy individuals (5.4%; 95% confidence interval, 2.0% to 11.3%; chi-square test; p = .022). There was no difference in tHcy plasma concentrations in the first 24 hrs after admission to an intensive care unit between survivors and nonsurvivors. The 5,10-methylenetetrahydrofolate reductase 677C-->T polymorphism had no influence on tHcy levels and survival of intensive care unit patients. CONCLUSIONS The prevalence of hyperhomocysteinemia is increased in critically ill patients compared to age- and gender-matched healthy individuals. The clinical significance of this finding remains to be determined.