A scavenger receptor of the B class (SR-BI)/human homolog of SR-BI, CD36, and LIMP II analogous-1 (CLA-1), has been identified as a receptor for high-density lipoprotein (HDL). Mice lacking SR-B1 develop anemia, plausibly explained by the observation that the erythrocyte life-span in these animals is reduced. Erythropoietin (EPO) is known to promote survival of erythroid cells, in large part through protection from apoptosis. We have examined the role of EPO on hSR-BI/CLA-1 expression and erythrocyte apoptosis. Endogenous expression of hSR-BI/CLA-1 was increased by exposure to EPO. EPO increased transcriptional activity of hSR-BI/CLA-1 promoter. The stimulatory effect of EPO on hSR-BI/CLA-1 promoter activity was abrogated by LY294002, specific inhibitor of phosphatidylinositol-3 kinase (PI3K). Constitutively active Akt stimulates the activity of the hSR-BI/CLA-1 promoter and a dominant-negative mutant of Akt abolished the ability of EPO to stimulate promoter activity. Finally, EPO in combination with HDL protected the cell from apoptosis, which suggests that hSR-BI/CLA-1 induced by EPO might contribute to the erythrocyte life-span.