Background: Carotid intima-media thickening (IMT) is a good surrogate for atherosclerosis and CVD. Previously we used the IMT response of inbred mouse strains to disturbed flow (d-flow) in the partial carotid ligation (PCL) model to identify an intima modifier locus Im3. Microarray and QTL analysis revealed ribosomal protein large subunit (RpL17) as the primary candidate gene for IMT within Im3; further, low RpL17 levels correlate with enhanced intima formation. RpL17 is located in the nascent protein exit tunnel, and serves as a docking site for the NAC chaperone in protein folding. We generated endothelial cell (EC)-specific conditional heterozygous RpL17 mice (EC-RpL17+/-, termed EC-RpL17) to study the IMT response to d-flow using PCL. Results: EC-RpL17 mice had increased IMT relative to controls (RpL17+/+) after PCL. Data showed induction of oxidative stress and endoplasmic reticulum (ER) stress in EC-RpL17 with activation of the integrated stress response (ISR), a stress-support pathway promoting hyperproliferation in cancer, including: 1) increased levels of reactive oxygen species (ROS), BiP, Chop, and Atf4 expression, activation of PERK (p-PERK), and inactivation of eIF2 alpha (p-eIF2 alpha) in cultured RpL17 microvascular EC. The in vitro data correlated well with in vivo data from post-PCL carotid immunostaining, including: increased p-PERK, BiP, Chop, 4-hydroxynonenal and 8-hydroxyguanosine. EM analysis revealed dilation of the rough ER (indicating ER stress), and decreased cytosolic polyribosomes in EC-RpL17 EC. Conclusion: Decreased EC RpL17 increases d-flow mediated IMT, likely due to induction of growth-promoting ISR by ER and oxidative stress. These data define a novel pathophysiological role for RpL17.