In the hamster to rat liver transplant model, we determined the efficacy of tacrolimus in attenuating natural xenospecific humoral immunity and in abrogating the hyperacute liver rejection that is produced by presensitizing the Lewis rat recipient. Hamster livers, transplanted orthotopically into naive rats (controls), were rejected with animal death after 6.4.+/- 0.5 (SD) days. The infusion on (day -6) of 1.5 x 10(7) hamster hepatocytes, or of 1.5 x 10(8) nonparenchymal cells (NPC), resulted in hyperacute rejection and death in < or = 1.9 days. However, when the rats were pretreated with 1 mg/kg/day tacrolimus from days -6 to -1, survival of non-presensitized animals was prolonged to 25 +/- 20 days and that of recipients presensitized with hamster hepatocytes to 36 +/- l6 days or with NPC to 32 +/- 1.7 days. The tacrolimus pretreatment significantly reduced the hamster-specific complement-dependent cytotoxic antibodies response directed to liver NPC but not to lymph node cell targets. These observations suggest that the prolongation of survival by appropriately timed treatment with this T cell directed drug model is caused by the inhibition of humoral as well as cellular xenograft rejection.