Significance Fatal cases of yellow fever are preceded by the development of hemorrhagic complications. While yellow fever virus is known to infect hepatocytes, the relationship between hepatocyte infection and the development of hemorrhage is currently undefined. Here, we identified high concentrations of D-dimer in the blood of yellow fever patients, indicative of a process that involves the activation and consumption of clotting factors. We then developed a mouse model in which only transplanted human hepatocytes could be infected at high levels. By examining clotting parameters in this model, we determined that hepatocyte infection alone is insufficient to cause the activation and consumption of coagulation factors observed in severe cases of yellow fever in humans and nonhuman primates.