A postmenopausal female evaluated for thrombophilia because of bone infarcts had mild hyperhomocysteinemia, which increased when hormone replacement was discontinued. Serum folate, cobalamin and methylmalonic acid were normal. Compound heterozygosity for C677T/A1298C methylenetetrahydrofolate reductase polymorphisms was present but oral folic acid failed to lower homocysteine and actually increased methylmalonic acid. Oral cobalamin therapy increased serum cobalamin and partially decreased methylmalonic acid but had no effect on homocysteine. Homocysteine remained unchanged after 11 months of oral cobalamin, folic acid and pyridoxine therapy. However, intramuscular cobalamin promptly decreased both metabolites to normal. Thus, parenteral cobalamin therapy may have greater metabolic effects than oral vitamin therapy even in apparently normal subjects.