In situ-perfused rat livers were infused with a single dose of 1.5 ؋ 10 7 radiolabeled cells of Leptospira interrogans serovar icterohaemorrhagiae, the agent of leptospirosis, or with Borrelia burgdorferi IRS, the agent of Lyme disease. Significant (P < 0.0001) differences in the liver uptake of L. interrogans and of B. burgdorferi were observed, the uptakes being 37.4% ؎ 2.3% for L. interrogans and 60.5% ؎ 3.1% for B. burgdorferi. Leptospires, in contrast to borreliae, were recovered from the livers when liver samples were cultured in growth medium. Leptospires but not borreliae were recovered in bile within 30 min of infusion. The association of leptospires and borreliae with reticuloendothelial cells of the liver was demonstrated by immunohistochemistry. Leptospires and borreliae were found to be associated with vimentin-positive cells and not with desminpositive cells. Few leptospires but no borreliae were also seen associated with vimentin-and desmin-negative cells, suggesting the presence of leptospires outside the sinusoidal spaces, in the liver parenchyma.The spirochetes Borrelia burgdorferi and Leptospira interrogans are the etiological agents of Lyme disease and leptospirosis, respectively. Despite substantial biological differences among human spirochetes, all spirochetoses share a spirochetemic phase during the early stage of infection (6,17,20,22). Leptospires can cause hepatitis in humans. This will result in microscopic alteration in the liver, including swelling of parenchymal cells, disruption of the liver cord, enlargement of Kupffer cells, and bile stasis in biliary canaliculi (2). In Lyme disease, liver function test abnormalities are common but mild and are most often not associated with symptoms (12). Lyme disease presenting as hepatitis and jaundice has been also reported (8). The involvement of the hepatic reticuloendothelial system (RES) in host defense by phagocytosis and killing of blood-borne spirochetes has been previously demonstrated in animals. Studies by us (18) have shown significant differences in the rat liver uptake of borreliae causing Lyme disease and of borreliae involved in relapsing fevers and have also indicated that B. burgdorferi is efficiently taken up by hepatic macrophages in the absence of serum factors. Electron microscopy studies by Faine (10) showed that in experimentally infected mice leptospires are found almost entirely in Kupffer cells and also interstitially between or in parenchymal liver cells.The perfused liver has been used several times in the past few decades to study bacterial hepatic phagocytosis (5, 13, 15). We therefore used such a technique to evaluate the uptake and killing of leptospires in comparison with borreliae by the rat hepatic RES in the elimination of circulating bacteria. Although the mouse is a widely used model for experimental infections with borreliae, this study was performed with rats, since they are more suitable for liver perfusion. The applicability of rats for experimental studies on borreliae has also been shown previously...