Hyperhomocysteimia, either fasting or after oral methionine loading, appears to be an independent risk factor for coronary heart disease (CHD). It remains unclear whether fasting total homocysteine determination alone adequately detects the full spectrum of hyperhomocysteinemic individuals. We measured fasting and 4-h post methionine loading (0.1 g L-methionine/kg body weight) total plasma homocysteine in 274 participants in The NHLBI Family Heart Study, a population-based investigation of genetic and non-genetic determinants of CHD. Of the total number (n = 47) of hyperhomocysteinemic persons, 43% (20/47) were identified only by methionine loading, while 32% (15/47) of the total number, and 75% of those with post-methionine loading hyperhomocysteinemia only (15/20), had fasting total homocysteine concentrations below the 75th percentile (10.7 mumol/l). We conclude that fasting total plasma homocysteine determination alone fails to identify a sizable percentage (> 40%) of persons who may have clinically relevant hyperhomocysteinemia post methionine loading.