To study helper T cell activation against minor histocompatibility (mH) antigens of the host after HLA-identical bone marrow transplantation, patients' lymphocytes collected longitudinally after transplantation were tested in a primed lymphocyte test using PBL from patients and donors as stimulator cells. Sixteen patients were studied between 1 and 25 months after grafting. Antihost Th cells were detected in 10 patients. Optimum levels of antihost activity were generally reached within the first 3 months, thereafter two patterns were identified; in some patients the antihost Th cell activity persisted for at least 2 years, whereas in other patients a decline was observed with time. Antihost Th cell activity developed in each of 5 patients with acute GVHD, in 3 out of 5 patients with chronic GVHD, but in only 2 out of 6 patients without GVHD. The average antihost Th cell activity in patients with acute GVHD was significantly higher than in patients without GVHD (P = 0.036) and was also higher, although not significantly, than in patients with chronic GVHD. These findings indicate that, in man, as was shown in studies in mice, helper T cells do participate in the response to mH antigens. Although other mechanisms may also be involved, we here propose that mH antigen-specific Th cells may be a risk factor for acute GVHD.