Given the weight of the evidence supporting homocysteine = s causative association with vascular disease, it is imperative to develop an accurate screening test for individuals at risk. To this end, we determined the prevalence of fasting hyperhomocysteinemia and the prevalence of post-methionine load hyperhomocysteinemia in 125 coronary artery disease (CAD) patients with normal lipids, 27 angiographically normal controls, and 4 obligate heterozygotes for cystathionine b-synthase (CBS) deficiency. Fasting hyperhomocysteinemia was defined as a fasting plasma homocysteine greater than 14.2 mmol/L (greater than 2 standard deviations above the mean fasting homocysteine in controls who had plasma B 1 2 > 200 pmol/L [n = 17]). Post-load hyperhomocysteinemia was defined as a rise in homocysteine, following methionine load, of greater than 26.7 μmol/L (greater than 2 standard deviations above the rise in controls). Collectively, fasting hyperhomocysteinemia was documented in 30% of subjects (33% of CAD subjects, 19% of controls, 50% [2 of 4] of CBS heterozygotes). Abnormal methionine load responses were seen in 8% of subjects, collectively (7% of CAD subjects, 4% [one of 27] of controls, and 75% [3 of 4] CBS heterozygotes). Of individuals with abnormal methionine loads, 75% also had fasting hyperhomocysteinemia. All of these individuals had plasma B 1 2 levels < 255 pmol/L, suggesting impairment of the remethylation pathway of homocysteine metabolism. The individuals with abnormal methionine loads and normal fasting homocysteine represented only 2% of all subjects. Given the low prevalence of isolated post-load hyperhomocysteinemia, and given that there is little published evidence to suggest that increased cardiovascular risk is conferred by isolated post-load hyperhomocysteinemia, we argue in favor of a single fasting homocysteine measurement as an adequate screen for individuals at risk for vascular disease due to homocysteine.