The anti-allograft immune response may have a cellular and a humoral component. Lymphocytotoxic antibodies (Ab) and anti-human leucocyte antigen (HLA) Ab present before kidney transplantation carry an enhanced risk of acute rejection. Current immunosuppressive drugs act predominantly upon the cellular immune pathway which may leave unopposed the humoral mechanisms of anti-allograft response. We studied the production of lymphocytotoxic Ab and anti-HLA Ab after kidney transplantation under different drug therapies. Two hundred and sixty-four consecutive kidney transplant recipients treated with different immunosuppressive drugs, either stable and or with previous acute rejection or acute urologic obstruction, entered this study. Lymphocytotoxic Ab and anti-HLA Ab were evaluated by complement-dependent cytotoxicity and by ELISA. Ab donor-specificity was determined by flow cytometry. Both lymphocytotoxic Ab and anti-HLA Ab were significantly increased in acute rejection whatever the immunosuppressive regimen and almost significantly in urologic obstruction treated with azathioprine (AZA) groups. The presence of antidonor-specific Ab was associated with a significantly higher rate of graft loss. Mycophenolate mofetil (MMF) therapy significantly down-regulated Ab synthesis in all patients groups when compared with AZA. The development of humoral antidonor response post-transplantation is associated with a dismal graft prognosis. This is the first report that acute urologic obstruction may be followed by unspecific lymphocytotoxic and anti-HLA Ab synthesis, surmising that a protracted obstruction may promote renal fibrosis through antibody mediation. The significant down-regulation of the humoral response by MMF when compared with AZA may herald a lower risk to mount a chronic rejection process.