Patients with hematological malignancies undergoing allogeneic marrow transplantation from HLA-identical siblings were entered into a randomized study to determine whether the prophylactic administration of horse anti-human thymocyte globulin (ATG) would decrease the incidence or severity of graft-versus-host disease (GVHD). Patients were conditioned with high-dose cyclophosphamide and total body irradiation before grafting and received methotrexate after grafting. When marrow engraftment was documented (median 16.5 days after transplantation), patients were randomized either to receive or not to receive horse ATG, 7 mg/kg, i.v., every other day for six doses. Twenty-nine patients received ATG and 27 patients did not. Both groups were comparable with respect to diagnoses, disease status, age, sex, donor-recipient sex match, and supportive care. Administration of ATG was associated with fever and chills in most patients, but was otherwise well tolerated. Patients receiving ATG had no delay in recovery of peripheral granulocyte or platelet counts, did not require increased platelet support, and did not have more infectious complications. No significant difference in either incidence or severity of GVHD was noted between patients receiving and those not receiving prophylactic ATG, although GVHD, if it developed, tended to be less severe among patients receiving ATG. Survival and causes of death were also comparable between groups. Thus, administration of horse ATG after documentation of marrow engraftment in recipients of HLA-identical allogeneic marrow grafts had neither significant toxicity nor beneficial effect.