Detailed information was sought on the capacity of purified Lyt-2+ cells to mediate lethal graft-versus-host disease (GVHD) directed to class I H-2 differences. When B6 Lyt-2+ cells were transferred to irradiated class I-different (B6 x bm 1)F1 mice, three different patterns of lethal GVHD were observed. First, rapid death from hematopoietic failure occurred when Lyt-2+ cells were transferred together with host-type marrow cells; this form of GVHD probably reflected direct destruction of stem cells by Lyt-2+ cytotoxic cells. Second, a pattern of late-onset, chronic GVHD resulting in death only after 4-6 wk occurred when Lyt-2+ cells were supplemented with donor marrow. This syndrome developed in the apparent absence of L3T4+ cells and was observed with either high or low doses of Lyt-2+ cells and with either light or heavy irradiation of the host. Third, an acute form of GVHD resulted when Lyt-2+ cells plus donor marrow cells were supplemented with exogenous help, i.e., by adding small doses of donor L3T4+ cells or injecting the hosts with rIL-2. Although L3T4+ cells potentiated GVHD when injected in small doses, supplementing Lyt-2+ cells with large doses of L3T4+ cells paradoxically led to marked protection; symptoms of GVHD were mild and no deaths occurred.