Homocysteine is an intermediate amino acid formed during the metabolism of methionine, a sulfur-containing essential amino acid, and cleared by the kidneys. The two major acquired causes of increased homocysteine values are chronic renal failure and absolute or relative deficiencies of folate, vitamin B12 or vitamin B6, three vitamins involved in the normal metabolism of methionine. We studied 176 patients (97 men and 79 women with mean age 56.3 +/- 14.8 years) with end-stage renal disease on peritoneal or hemodialysis. Homocysteine concentrations averaged 26.6 +/- 1.5 mumol/liter in patients with renal failure as compared to 10.1 +/- 1.7 mumol/liter in normals. Abnormal values exceeded the 95th percentile for normal controls in 149 patients, giving an overall prevalence of homocysteinemia of 85%. There was preservation of the negative correlation between homocysteine and folate (r = -0.48), suggesting responsiveness in spite of impairment. Increased homocysteine concentrations were associated with an increased odds ration for atherosclerotic and thrombotic complications independent of other traditional risk factors and the length of time on dialysis. The odds ratio for vascular events with homocysteine levels was 2.9 (CI 1.4 to 5.8) for the upper two quintiles of homocysteine values compared to the lower three quintiles adjusted for age, gender, hypertension, diabetes, hypercholesterolemia, smoking and time on dialysis. These data indicate that plasma homocysteine values represent an independent risk factor for vascular events in patients on peritoneal and hemodialysis. The mechanism by which high homocysteine concentrations might cause vascular damage in patients with renal failure remains unclear.