High levels of plasma homocyst(e)ine (H[e]) are associated with increased vascular risk. Treatment is being contemplated, but the level at which patients should be treated is not known. We compared the response of carotid plaque to vitamin therapy in patients with H(e) above and below 14 micromol/L, a level commonly regarded as high enough to warrant treatment. Two-dimensional B-mode ultrasound measurement of carotid plaque was used to assess the response to vitamin therapy with folic acid 2.5 mg, pyridoxine 25 mg, and cyanocobalamin 250 microg daily, in 101 patients with vascular disease (51 with initial plasma levels above, and 50 below 14 micromol/L). Among patients with plasma H(e) >14 micromol/L, the rate of progression of plaque area was 0.21 +/- 0.41 cm2/year before vitamin therapy, and -0.049 +/- 0.24 cm2/year after vitamin therapy (P2 = .0001; paired t test). Among patients with levels <14 micromol/L, the rate of progression of plaque was 0.13 +/- 0.24 cm2/year before vitamin therapy and -0.024 +/- 0.29 cm2/year after vitamin therapy (P2 = .022, paired t test). The change in rate of progression was -0.15 +/- .44 cm2/year below 14 micromol/L, and -0.265 +/- 0.46 cm2/year above 14 micromol/L (P = 0.20). Vitamin therapy regresses carotid plaque in patients with H(e) levels both above and below 14 micromol/L. These observations support a causal relationship between homocyst(e)ine and atherosclerosis and, taken with epidemiologic evidence, suggest that in patients with vascular disease, the level to treat may be <9 micromol/L.