BALB/c spleen cells were incubated with a solubilized membrane fraction (SMF) prepared from spleen and thymus cells of (BALB/c × C3H/He)F, or (BALB/c × A/J)F, hybrid mice. Cells incubated with (BALB/c × C3H/He)F, SMF produced less graft-versus-host (GVH) splenomegaly in (BALB/c × C3H/He)F, hosts than did untreated BALB/c cells. The reduction of GVH splenomegaly was specific, inasmuch as the GVH activity of (BALB/c × C3H/He)F, SMF-treated and untreated cells was similar in (BALB/c × C57BL)F1 hosts, and BALB/c cells treated with (BALB/c × A/J)F, SMF showed no alteration of GVH activity in either (BALB/c × C3H/He)F, hosts or (BALB/c × C57BL) F, hosts. The time course of splenomegaly did not differ for SMF-treated and untreated cells. Donor cells that were labeled with tritiated adenosine and treated with (BALB/c × C3H/He) F, SMF produced a reduction in the amount of label appearing in (BALB/c × C3H/He)F1 host spleens but not in (BALB/c × C57BL)F1 host spleens. Mechanisms which could account for the ability of SMF to cause specific reductions in both GVH activity and host spleen labeling are discussed.