Background. Cyclosporine (CsA) is an essential posttransplantation immunosuppressive drug. It may cause hepatotoxicity, mostly cholestasis, by unknown mechanism. CsA causes nephrotoxicity mainly by increased vascular resistance. We investigated the effects of CsA on the peribiliary capillary plexus, in an isolated, dually perfused (i.e., via the hepatic artery and the portal vein) rat liver preparation. Methods. After 30 min of stabilization with optimal flow (4 ml/min/g liver), four liver groups were perfused (control, n=5 each) and four groups were hypoperfused (n=5 each, 1 ml/min/g) for 120 min. This was followed by a 30-min optimal reperfusion phase, during which the controls and the hypoperfused groups were injected (60 sec) via the hepatic artery with CsA at high (3 mg/kg body weight in 1 ml) or low dose (0.03 mg/kg), cremophore (130 mg/kg), or saline (1 ml). A ninth group (n=5) underwent 2-hr ischemia and 30-min reperfusion to standardize liver damage. Dark nonradioactive microspheres (similar to 10 mu m diameter) were injected via the hepatic artery 15 min after drug or saline injection. Results. Neither of the two CsA doses, nor cremophore controls, nor hypoperfusion alone caused entrapment of microspheres in the peribiliary circulation as assessed by light microscopy; perfusion pressures and resistances were also not altered. Significant arteriolar impaction and vasculature engorgement occurred in the hypoperfused plus high-dose CsA livers; hypoperfusion plus low-dose CsA or cremophore groups were minimally tainted. Vascular notable obstruction was associated with 15-40% increase in portal and arterial perfusion pressures and resistances, 50% decrease in oxygen extraction, and increase in lactate/pyruvate ratio, hepatocellular damage, and wet-to-dry weight ratio. Such findings were superior to those detected in the ischemic livers. Conclusions. Acute single high-dose CsA injection, but not low-dose or cremophore, if combined with decreased flow, alters hepatic microcirculatory resistance. Possible correlations between such changes and clinical implications in organ transplantation are discussed.