Transplantation of a Lewis rat small bowel allograft (SBTx) into Lewis x Brown Norway F1 (LBNF1) hybrid recipients provokes lethal graft-versus-host disease. GVHD in F1 hybrid rats inoculated with large number of parental lymphocytes may be abrogated by prior treatment of F1 hybrids with a sublethal dose (SLD) of the same parental lymphocytes. Therefore, we sought to determine whether this type of immunomodulation would prevent GVHD after SBTx. We examined whether pretreatment of LBNF1 recipients with a SLD of parental lymphocytes, or with a revascularized segment of parental small bowel, might ameliorate GVHD following transplantation of the entire parental small bowel. Nonpretreated LBNF1 recipients died of GVHD after entire Lew SBTx; 95% of LBNF1 recipients pretreated with SLD of Lew lymphocytes and 84% of LBNF1 recipients first transplanted with a segment of Lew small bowel survived GVHD induced by entire Lew SBTx 10 days later. Of LBNF1 recipients pretreated with SLD of Brown Norway lymphocytes or first transplanted with a segment of BN small bowel, none were protected from GVHD induced by entire Lew SBTx 10 days later. We concluded that pretreatment of LBNF1 recipients either with an SLD of parental lymphocytes or with a segment of parental small bowel provides profound protection from the effects of GVHD following transplantation of an entire small bowel of the same parental strain specificity.