Cell transplantation-induced hepatic ischemia and recruitment of vasoconstrictors, e.g., endothelin-1, leads to clearance of transplanted cells and poses problems for liver repopulation. Therefore, we determined whether darusentan, which potently blocks endothelin-1 receptor type A, could benefit cell engraftment. We transplanted primary F344 rat hepatocytes with or without darusentan in dipeptidyl peptidase IV-deficient rats. Analysis of microcirculatory events included hepatic ischemia, endothelial injury, including with gene expression arrays, and activations of Kupffer cells, neutrophils or hepatic stellate cells. The retrorsine-partial hepatectomy model was used for liver repopulation studies. Whether darusentan was directly cytoprotective was examined in cultured rat hepatocytes or CFSC-8B rat hepatic stellate cells. We found darusentan induced hepatic sinusoidal vasodilation, caused more transplanted cells to be deposited in liver parenchyma, and decreased hepatic ischemia and endothelial injury. This lessened perturbations in expression of endothelial biology genes, including regulators of vessel tone, inflammation, cell adhesion, or cell damage versus drug-untreated controls. Moreover, in darusentan-treated animals, cell transplantation-induced activation of Kupffer cells, albeit not of neutrophils, decreased, and fewer hepatic stellate cells expressed desmin. In darusentan-treated rats, improvements in cell engraftment led to greater extent of liver repopulation compared with drug-untreated controls. In cell culture assays, darusentan did not stimulate release of cytoprotective factors, such as vascular endothelial growth factor, from hepatic stellate cells. Moreover, darusentan did not protect hepatocytes from TNF-α- or oxidative stress-induced toxicity. Endothelin receptor A blockade in vitro did not improve engraftment of subsequently transplanted hepatocytes. We concluded that systemic administration of darusentan decreased hepatic ischemia-related events and thus indirectly improved cell engraftment and liver repopulation. This vascular mechanism will permit development of combinatorial drug-based regimens to help optimize cell therapy.