Mild acute rejection progresses to moderate rejection in approximately one third of the cases. Standard rejection therapy would then be instituted with the attendant risk of infection and other side effects. We randomized 40 episodes of mild acute rejection (20 episodes in each group) to receive no additional therapy or to have the oral cyclosporine dose increased for 7 to 10 days with repeat endomyocardial biopsy performed. In the group with no additional therapy 30% progressed to moderate rejection, whereas in the group with increased doses of oral cyclosporine, 10% progressed to moderate rejection (p = 0.10). As the purpose of our study was to assess the efficacy of increased cyclosporine levels for preventing progression from mild to moderate rejection, the treated group was redefined according to whether the cyclosporine level increased by greater than or equal to 50% during the study. In this treated group average cyclosporine levels increased from 169 +/- 78 to 413 +/- 267 ng/ml. Progression to moderate rejection occurred in one of 21 cases (5%) compared with seven of 19 cases (37%) in the group without an increase in cyclosporine level (p less than 0.05). The transient increase in cyclosporine levels was well tolerated. This study demonstrates that the use of high dose oral cyclosporine to treat mild acute rejection is well tolerated and may reduce progression to moderate rejection when a significant increase in cyclosporine level is achieved.