Homocysteine is implicated to be an atherogenic amino acid and has been associated with increased risk of adverse cardiovascular outcomes. The prognostic significance of plasma total homocysteine (tHcy) levels for mortality and allograft loss in kidney transplant recipients has not been established. A total of 733 kidney transplant recipients who were seen for a routine visit at this transplant clinic in 1996 to 1998 were studied prospectively. During that visit, clinical information was collected and blood was drawn for laboratory evaluation. Information on the previous transplant procedure and the organ donor was obtained from the Eurotransplant Foundation database. Patients were followed prospectively using the Austrian Dialysis and Transplant Registry. With the use of proportional-hazards regression, the independent relations of fasting plasma tHcy levels to the risk of death from any cause and kidney allograft loss were examined. During a median follow-up of 6.1 yr, 154 participants died and 260 kidney allografts were lost. After adjustment for several important risk factors, elevated tHcy levels (>/=12 micromol/L) were associated with 2.44 times the mortality risk of patients with normal tHcy levels (hazards ratio 2.44; 95% confidence interval 1.45 to 4.12; P < 0.001). Similarly, elevated tHcy levels were associated with 1.63 times increased risk of kidney allograft loss (hazards ratio 1.63; 95% confidence interval 1.09 to 2.44; P = 0.02). In this single-center sample, baseline fasting plasma tHcy levels were independently associated with the risk of death and kidney allograft loss. The clinical utility of homocysteine-lowering therapy, such as multivitamin therapy, to reduce the rates of these end points needs to be studied.