Cells of the monocyte/macrophage system originate from the bone marrow, reach the organs via the blood, immigrate through postcapillary venules and further differentiate into organ-specific tissue macrophages. In rats and other species, activated monocytes/macrophages aggravate autoimmune reactions, rejection of non-vascularized allografts and chronic allograft rejection. It is very likely that they also contribute to acute allograft destruction. So far it has been impossible to distinguish the function of monocytes from that of macrophages, because cell phenotypes and their alterations upon activation are ill-defined. We have thus begun to characterize the ex vivo phenotype and function of rat monocytes in the normal state and during renal allograft rejection. Monocytes are recovered from both the central and the marginal blood pool by perfusing either the recipient's circulation or the allograft vasculature. Rat monocytes have a unique surface phenotype. During allograft rejection or after infusion of interferon-gamma they up-regulate class II MHC molecules, CD161 (NKR-P1A), CD62L and CD8, while CD4 and CD43 are down-modulated. Activated perfusate monocytes exert increased in vitro cytotoxicity against tumour targets, which differs from that of NK cells. We speculate that activated monocytes contribute to kidney allograft destruction by directly damaging endothelial cells or by promoting intravascular coagulation.