We have examined the role of donor natural killer (NK) cells in various forms of local and systemic graft-versus-host reaction (GvHR), by using beige mouse lymphocytes as the donor cell population. In contrast to lymphocytes from normal, congenic C57Bl/6 (B6) mice, beige spleen cells could not induce either an acute, lethal GvHR or a proliferative form of GvHR in adult, unirradiated F, hybrid hosts. In addition, beige donor cells produced little GvHR in the popliteal lymph node after local transfer and caused less severe and less sustained intestinal GvHR in unirradiated hosts. However, beige cells were fully capable of inducing a lethal GvHR in irradiated hosts. These studies indicate that beige mice have a defective ability to induce many types of GvHR, but suggest that this is a quantitative abnormality rather than an absolute lack of responsive cells. We propose that this may reflect a defect in T-cell function rather than a pure NK cell defect.