BACKGROUND Epicardial vasculopathy has been shown to be associated with poor outcome after heart transplantation. We demonstrate that histologically proven stenotic microvasculopathy is a novel prognostic factor for long-term survival. RESULTS In 9713 biopsies harvested within the first posttransplantation year from 873 patients (83% male; mean age, 49.1+/-0.6 years), light microscopic evaluations (x200) were performed for microvasculopathy, defined as stenotic endothelial and/or medial disease. Prevalence of severe epicardial vasculopathy was defined by presence of > or = 75% luminal stenosis in coronary angiography (available in 611 of 873 patients), which was present in 118 of 611 patients (19%). For Kaplan-Meier analysis, we defined fatal cardiac events as lethal acute myocardial infarction, sudden cardiac death, and graft failure. Stenotic microvasculopathy was present in 379 of 873 patients (43%) and was due to medial (345/379; 91%) rather than endothelial disease (2/379; 1%) or a combination of both (31/379; 8%; P<0.001). Endothelial disease (median [95% CI], 12.07 [10.69 to 13.44] versus 12.73 years [10.16 to 15.30]; P=0.3329) and nonstenotic medial disease (12.44 [11.14 to 13.74] versus 12.43 years [10.51 to 14.35]; P=0.4047) did not decrease overall survival or time to fatal cardiac event. Stenotic microvasculopathy was associated with poor overall survival (10.90 [9.16 to 12.60] versus 13.40 years [11.79 to 15.07]; P=0.0374) and decreased freedom from fatal cardiac events (1, 5, 10 years, 95.6+/-1.4%, 86.9+/-2.3%, 75.5+/-3.1% versus 99.1+/-0.5%, 96.8+/-1.0%, 89.8+/-1.9%; P<0.0001). This finding was independent of epicardial transplant vasculopathy (P=0.0031). CONCLUSIONS Stenotic microvasculopathy is frequent in routinely processed biopsies and a new prognostic factor for long-term survival after heart transplantation.