Several studies have reported that moderate hyperhomocysteinemia is related to an increased risk for atherosclerosis, but few data are available with regard to any other thiol compound having a potential vascular toxicity. Therefore, we measured both total cysteine and homocysteine plasma levels in patients with hyperlipidemia (242 males and 147 females, 41-65 years old). Homocysteine was higher in males than in females, 13.2+/-4.1 versus 11.1+/-3.4 micromol/l (P<0.0001). The mean cysteine level was 243.3+/-45.7 micromol/l in the whole study population. The subjects were split in two groups, symptomatic patients with cardiovascular disease (n = 106) and asymptomatic subjects (n = 283). Blood pressure, smoking status, total cholesterol, LDL-cholesterol and triglycerides did not statistically differ between groups, but the mean HDL-cholesterol level was lower in symptomatic patients (1.24+/-0.38 versus 1.42+/-0.41, P<0.0001). Cysteine levels were higher in patients with cardiovascular disease than in asymptomatic patients, respectively 254.7+/-47.7 versus 239.1+/-44.3 micromol/l (P = 0.003). A similar result was found for homocysteine, respectively 13.1+/-4.3 versus 12.2+/-3.9 micromol/l (P = 0.05). To analyse whether cysteine levels were related to atherosclerosis independently of age, adjusted levels were compared between asymptomatic patients with normal carotid arteries (n = 176), carotid atherosclerosis (n = 107) and symptomatic patients (n = 106). Age adjusted cysteine levels differed significantly between groups (P = 0.027) while the P-value was of borderline significance for homocysteine (P = 0.09). Odds ratios for having symptomatic cardiovascular disease were 1.81 (95% CI, 1.02-3.21) and 2.05 (95% CI, 1.16-3.60) for the mid and highest tertiles of cysteine using the lowest as the reference. After adjustment in a multivariate model including age, sex, and creatinine, the odds ratio for disease remained significant between the highest tertile versus the lowest (OR = 1.89). Adjusted odds ratios were found to be weaker when homocysteine tertiles were compared. Our data suggest that plasma total cysteine is a risk factor for atherosclerosis in hyperlipidemic patients.