Chronic graft-v-host disease (GVHD) is the most frequent late complication of allogeneic bone marrow (BM) transplant. To test different treatments, we used a rat model of chronic GVHD which clinically, histologically, and immunologically resembles the disease occurring after human marrow transplant. The following treatments were administered: azathioprine 50 mg/kg/day plus prednisone 1 mg/kg/every other day; Cyclosporine (CsA) 30 mg/kg/day; CsA 30 mg/kg/day plus prednisone 1 mg/kg/every other day; thalidomide 50 mg/kg/day; thalidomide 10 mg/kg/day; CsA 10 mg/kg/day; and thalidomide 10 mg/kg/day plus CsA 10 mg/kg/day. All drugs were administered by gavage. Half of the animals (six of 12) treated with azathioprine plus prednisone every other day responded to treatment. The majority of animals (seven of 12) treated with CsA died early. The addition of prednisone every other day did not improve survival. The surviving animals treated with CsA (with or without prednisone) responded to treatment. Half of the animals treated with each of the above regimens had recurrent or progressive disease after therapy was discontinued. Thalidomide treatment was successful in the majority of animals (16 of 18). The addition of low-dose CsA to low-dose thalidomide resulted in a faster rate of response (12.1 +/- 1.8 v 28.2 +/- 1.6 days). We conclude that both thalidomide and thalidomide plus CsA appear promising in this model as treatment for chronic GVHD.