To determine whether plasma homocysteine concentrations are increased in patients after cardiac transplantation. Total plasma homocysteine concentration was measured in 44 consecutive patients before and at 3, 6, and 12 months after orthotopic heart transplantation between June 1, 1988, and Oct. 15, 1992, and the data were analyzed statistically. Mean homocysteine concentrations (normal range, 4 to 17 μmol/L) increased 70% from 12.5 μmol/L before cardiac transplantation to 21.2 μmol/L (P<0.002) 3 months after transplantation, at which time the concentrations were above normal in 14 of 26 patients (54%). Homocysteine concentrations remained elevated 6 and 12 months after transplantation (20.4 and 22.6 μmol/L, respectively) but did not increase further. Mean concentrations of plasma folic acid and vitamin Bl2, cofactors in homocysteine metabolism, decreased 20% and 49%, respectively, within 3 months after transplantation (11.6 to 9.3 μg/L [P = 0.04] and 584 to 295 ng/L [P =0.01]). The mean glomerular filtration rate decreased 25% during this same interval (81 to 61 mL/min; P = 0.0001). Linear regression analysis revealed an association between the increase in homocysteine concentration and the folic acid concentration that approached statistical significance (P = 0.07); we found no statistically significant correlates of the increase in homocysteine concentration. The homocysteine concentration increases in most patients within 3 months after cardiac transplantation to levels previously associated with premature atherosclerotic coronary artery disease, and it remains increased for at least 1 year. Further investigation into the mechanism for the increase in homocysteine concentration and the relationship between homocysteine and coronary artery disease after transplantation is warranted.