We have examined the ability of highly purified subsets of C57B1/6 L3T4+and Lyt2+cells to cause intestinal graft-versus-host reactions in H-2 mutant mice expressing isolated class I (bm1) or II (bm12) MHC mutations.Heavily irradiated B6×bm12)F1mice given B6 L3T4+T cells (anti—class II GVHR) developed an acute, lethal GVHR that was associated with intense jejunal crypt hyperplasia and an early rise in the density of intraepithelial lymphocytes. Irradiated (B6xbml)F1mice given B6 Lyt2+T cells (anti-class I GVHR) showed a similar phase of crypt hyperplasia within the first 2 weeks, but this was less marked than for anti—class II GVHR and was not associated with an increase in IEL count. Only very minor gut pathology was observed when B6 Lyt2+T cells were transferred to irradiated mice carrying the bm9 class I mutation, which is much weaker than the bm1 mutation and does not stimulate Lyt2+helper T cells. The GVHR mediated by B6 L3T4+and Lyt2+T cells was H-2 class-specific, as no pathology was seen in bm12 recipients of Lyt2+cells or in bml recipients of L3T4+cells.B6 L3T4+and Lyt2+T cells both induced splenomegaly and intestinal GVHR in nonirradiated, 4–5-day-old neonatal (B6×bm12)F, or (B6×bm1)F1mice, respectively, a form of intestinal GVHR that does not require specific cytotoxic T lymphocytes. Again, Lyt2+T cells were less efficient than L3T4+T cells in the induction of GVHR.Thus, both class I and class II MHC-restricted T cells can mediate different forms of intestinal GVHR under appropriate circumstances, but class II MHC-restricted T cells may be more efficient.