Male Lewis strain rats underwent bile duct ligation and division (BDL), selective hepatic duct ligation (SHL), simple ligation and recanalization (RCN), or sham celiotomy (SC). Unoperated rats served as normal controls (NC). At intervals of 1, 2, and 3 weeks postoperatively, the popliteal lymph node assay was used to study host versus graft (HVG) response. LBN-F1 splenocytes (5 × 106) were injected into the hind foot pads, and the contralateral foot pad was injected with medium as a control. The popliteal lymph nodes were removed and weighed 7 days later. In the BDL group, HVG response was significantly impaired at 1 (BDL, 12,9 ± 5.1 mg; SC, 21.6 ± 2.6; NC, 22.4 ± 9.4; P < 0.005, BDL vs SC or NC), 2 (BDL, 12.6 ± 5.6; SC, 19.1 ± 3.0; NC, 15.8 ± 5.8; P < 0.001, BDL vs SC), and 3 weeks (BDL, 8.9 ± 3,9; SC, 21.7 ± 6.3; NC, 16.7 ± 3.8; P < 0.001, BDL vs SC or NC). SHL did not cause hyperbilirubinemia or impair the HVG response at 2 weeks (SHL, 17.2 ± 4.5; NC, 16.7 ± 7.4). The serum bilirubin was normal 2 and 3 weeks after RCN, and the HVG response was normal in both groups; however, the HVG response was somewhat lower at 2 weeks (RCN, 12.1 ± 2.1) than at 3 weeks (RCN, 18.2 ± 4.4; P ± 0,01, RCN 2 weeks vs RCN 3 weeks). BDL causes significant impairment in the murine response to alloantigens as measured by the popliteal lymph node assay. Preservation of sufficient normally drained hepatic parenchyma to prevent hyperbilirubinemia also preserves the HVG response, as does incomplete obstruction (RCN).