Hyperhomocysteinemia in cobalamin and folate deficiency reflects an imbalance between influx and elimination of homocysteine (Hcy) in plasma. We investigated the kinetics of total Hcy (tHcy) in plasma after peroral Hcy administration in 19 volunteers with hyperhomocysteinemia (mean +/- SD: 67.1 +/- 39.5 mumol/L; range: 23.5-142.8 mumol/L) before and after supplementation with cobalamin and/or folate. Vitamin therapy decreased plasma tHcy to 21.8 +/- 14.1 mumol/L (range: 9.6-57.9 mumol/L) but caused only a marginal decline in the area under the curve (AUC) by 8% and plasma half-life by 21%. Using the equations for steady-state kinetics, these data indicate that mean plasma tHcy clearance is normal and that massive export of Hcy from tissues into plasma is the major cause of hyperhomocysteinemia in cobalamin or folate deficiency. However, the spread in AUC and plasma half-life values was large in hyperhomocysteinemia subjects, suggesting marked individual variability in tHcy clearance. Plasma methionine after Hcy loading did not increase before (0.9 +/- 6.8 mumol/L) but increased normally (12.8 +/- 4.6 mumol/L) after vitamin therapy, and the methionine response discriminated between vitamin-deficient and vitamin-replete subjects. In cobalamin- or folate-deficient subjects, only 6.5 +/- 3.0% of the Hcy dose was excreted unchanged in the urine, demonstrating that urinary Hcy excretion does not explain normal tHcy plasma clearance in subjects with impaired Hcy remethylation. Our data suggest that hyperhomocysteinemia in folate and cobalamin deficiency is related to increased influx of Hcy to plasma, and that the methionine synthase function is not an important determinant of elimination of Hcy from plasma. The large interindividual difference in Hcy clearance may be explained by variable adaptation to impaired methionine synthase function through increased Hcy flux through alternate metabolic pathways.