The rejection of H-2b parental bone marrow graft by lethally irradiated F1 recipients, that is known as hybrid resistance (HR), is a multistep process. In a first step a 5-fluorouracil (5-FU)-sensitive T cell recognizes the parental bone marrow cells and stimulates a macrophage-like cell to secrete IFN-alpha/beta (recognition phase). IFN-alpha/beta in turn activates a cyclophosphamide-sensitive NK-like cell that is the effector cell for HR (effector phase). In a previous paper we described that HR is specifically abrogated by the pretreatment of the F1 recipient with H-2b parental spleen cells. This abrogation is due to a Thy-1+CD5+CD4+CD8- nylon adherent suppressor cell of F1 origin. The aim of the present work was to study during which of the different phases of HR the activity of the suppressor cell is exerted. Our results showed that abrogation of HR in (C57BL/6 x C3H)F1 (B6C3F1) hybrids pretreated with B6 spleen cells results from: 1) the suppression of the 5-FU-sensitive T cell; 2) the suppression of the cyclophosphamide-sensitive NK-like cell; and 3) the disappearance of a humoral factor that is present in the serum of normal B6C3F1 hybrids and which seems to be involved in the effector phase of HR. The 5-FU-sensitive T cell is the only target of Thy-1+CD5+CD4+CD8- suppressor cell. The mechanisms responsible for the suppression of the NK-like effector cell and the disappearance of the humoral factor are discussed.