Methionine (Met) loading increases total plasma homocysteine (tHcy) and assesses homocysteine metabolism. We tested the hypothesis that pre- or post-Met tHcy will predict recurrent stroke or coronary artery disease (CAD) in a subgroup analysis of the Vitamin Intervention for Stroke Prevention (VISP) trial. VISP subjects with non-disabling stroke underwent measurement of tHcy at baseline (fasting pre- and post-Met load) and were randomized to high/low-dose B-vitamin therapy for prevention of recurrent stroke or CAD. In the sample cohort of 2124 subjects, mean+/-S.D. tHcy levels in micromol/l were pre-Met 13.2+/-4.3, post-Met 30.4+/-9.76, and pre/post-Met Delta 17.1+/-8.3. The hazard ratio (HR) for recurrent stroke was 1.16 (p=0.026) for 1 S.D. higher pre-Met tHcy and 1.15 (p=0.054) for 1 S.D. higher post-Met tHcy. For CAD, the HR for 1 S.D. higher pre-Met tHcy was 1.27 (p=0.001) and was 1.00 (p=0.99) for post-Met tHcy. In survival analyses using pre- or post-Met as covariates, the coefficient of pre/post-Met Delta was not significant for stroke and was only marginally significant for CAD (p<0.08), but was negative. We conclude that fasting, pre-Met tHcy is as effective as post-Met tHcy or pre/post-Met Delta in predicting the risk for stroke and CAD.