Cyclosporine A (CsA) is linked with the development of transplant vasculopathy (TVP). We investigated the influence of different CsA regimens on TVP after rat heart transplantation. After heterotopic cardiac transplantation (Lewis to Fisher) animals were divided into 3 groups: controls (no therapy, n=20), 3mg-CsA (3mg/kg/d/s.c., n=50), 12mg-CsA (12mg/kg/d/s.c., n=50). In group 2 and 3 CsA treatment ended either at day 20, 40, 60 or 80. 5 animals each were killed 20, 40, 60 and 80 days after transplantation with the following distribution: no therapy, treatment until sacrification, treatment ending 20, 40 or 60 days before sacrification. CsA levels were determined every ten days and ten days after withdrawal. TVP was assessed by digitizing morphometry and expressed as mean vessel occlusion (mvo). Acute rejection was scored (ISHLT criteria). In 12mg-CsA animals CsA level was 5 to10 fold higher than in 3mg-CsA animals and undetectable 10 days after withdrawal in both groups. In control animals we found a score IV of acute rejection, in continuously treated animals IIa in 12mg-CsA and IIIa in 3mg-CsA animals. But already 20 days after the withdrawal of CsA no significance was found when compared to controls and there was no difference at the end of the study when a 20, 40 or 60-day course of CsA application (group 2 and 3) was compared with untreated controls. Both continuous CsA regimens reduced the mvo significantly when compared with controls. We found no significant difference between 12mg and 3mg. The withdrawal of CsA therapy lead to an increase of mvo to levels with no significant difference to control animals. Despite the excessive increase of CsA blood levels we found neither a further reduction nor an increase of mvo in the high dose group compared with the low dose regimen. Our data suggest that CsA is not responsible for the development of TVP and that high CsA-levels lead to the same extent of TVP as low levels do.