We assessed various immune responses against donor tissue to determine their value in the diagnosis and prediction of clinical rejection episodes. Twenty-six consecutive clinical renal-transplant recipients were examined. Cell-mediated lymphocytotoxicity preceded and accompanied 41 of 45 rejection episodes (P less than 0.001). Complement-dependent antibody was present in 12 of 15 rejections (P less than 0.002)--four not accompanied by, and eight in association with, cell-mediated lymphocytotoxicity. Mixed lymphocyte reactivity or nonreactivity and inhibition by autologous serum occurred equally often in rejection and quiescence. Lymphocyte-dependent antibody occurred during both rejection episodes and quiescent phases, with a greater frequency during quiescence (P = 0.05). Cell-mediated lymphocytotoxicity was the best predictor of rejection (P less than 0.05). Cell-mediated lymphocytotoxicity was the best predictor of rejection (P less than 0.001), and was more easily suppressed by standard immunosuppressive therapy, than complement-dependent antibody. If specific cell-mediated lymphocytotoxicity, with or without antibody, recurred after rejection therapy, the graft underwent further rejection.