Hepatocyte transplantation is a modality that is suggested for providing temporary hepatic support during periods of liver regeneration following acute hepatic failure. The immunologic response of canine recipients to intrasplenic hepatocyte allografts was studied. Canine hepatocytes are highly immunogenic, initiating a host response which destroyed the allograft within 1 wk post-transplantation (survival range 1-6 days, mean .+-. SD = 3.33 .+-. 1.86 days). Administration of azathioprine post-transplantation significantly (P < 0.01) extended the survival of the hepatocyte allografts (survival range 3-9 days, mean .+-. SD = 5.66 .+-. 2.16 days). Long-term survival was not seen using this type of minimal immunosuppression. Histologic observations confirmed these findings. Caution is recommended prior to the application of hepatocyte transplantation in humans.