Transplantation of T-cell depleted bone marrow has been associated with an increased risk of graft failure, requiring additional immunosuppression to prevent this complication. To determine the effect of graft rejection prophylaxis with posttransplant anti-thymocyte globulin and methylprednisolone on immune reconstitution, the lymphoid phenotype, function, and infectious complications of 170 recipients of a T-cell depleted bone marrow transplantation, 57 of whom received prophylaxis, were analyzed. Neutrophil recovery and normalization of T-cell numbers were more rapid in patients given anti-thymocyte globulin and methylprednisolone. Adults given graft rejection prophylaxis had prolonged inversion of their CD4/CD8 ratio, increased numbers of CD8+ CD11b+, HLA-DR+, CD57+, CD28-T cells, and delayed recovery of T-cell mitogen responses when compared to adults not given ATG and steroids. Even without posttransplant immunosuppression to prevent graft failure, adults experienced delayed recovery of total and CD45RA+ CD4+ cells, prolonged inversion of the CD4/CD8 ratio, and delayed recovery of T-cell mitogen responses when compared to children. During the first posttransplant year, Epstein-Barr Virus-Associated Lymphoproliferative disorders and opportunistic infections were increased in patients given prophylaxis. Patients who developed an opportunistic infection or EBV-LPD had significantly fewer circulating CD4+ T cells than those who did not. This study demonstrates that older age and graft rejection prophylaxis, rather than T-cell depletion alone, are associated with delayed immune reconstitution. In addition, it suggests that CD4 cell counts may be useful in predicting which patients are at increased risk of developing opportunistic infections following successful engraftment.