BACKGROUND A toxic and pro-oxidative effect of homocysteine on the coronary endothelium may accelerate cardiac allograft vascular disease (CAVD). In this study, we evaluated the influence of hyperhomocysteinemia on the course of CAVD. METHODS We investigated plasma homocysteine (tHCY) concentrations in 183 consecutive heart transplant recipients (158 men and 25 women, mean aged 53.1 +/- 10.0 years, at 6.7 +/- 3.2 years after transplantation) to evaluate the course of CAVD. We used serial coronary angiography to assess coronary status and graded the severity of CAVD based on the extent of luminal obstruction in the main coronary arteries (graded as 1-4). We defined progression as increased focal stenosis of >/=30% or as detection of a new coronary lesion after a mean observation period of 2.8 +/- 1.0 years. A multivariate analysis (backward logistic regression) was performed that included potential risk factors for CAVD. We excluded patients undergoing dialysis. RESULTS Initially, tHCY concentrations were increased in the entire cohort (mean, 18.6 +/- 7.6 mumol/liter) and ranged from 6.6 to 46.9 mumol/liter. A total of 105 patients (57.0%) had CAVD at first angiography, and progression was detected in 52 transplant recipients (28.0%). Patients with progressive CAVD had significantly greater tHCY concentrations (21.6 +/- 6.2 mumol/liter) at baseline investigation compared with patients who had stable courses (17.4 +/- 7.7 mumol/liter; p < 0.001). These results were independent of parameters such as sex, age, dyslipoproteinemia, cyclosporine blood concentrations, and indication for transplantation. CONCLUSIONS Progression of CAVD is strongly associated with increased tHCY concentrations. The intervals between routine surveillance angiography should be shortened in patients with hyperhomocysteinemia, and routine medical treatment to decrease homocysteine concentrations should be considered.