Abstract—Axl, a receptor tyrosine kinase, was recently identified as a novel candidate gene in a genetic model of salt-sensitive hypertension (Sabra rat). Our group first reported that Axl plays a significant role in vascular remodeling in response to injury. Here we investigated the role of Axl in the pathogenesis of hypertension in a deoxycorticosterone acetate (DOCA)–salt model. Hypertension was induced in Axl wild-type (Axl^+/+) mice and Axl-deficient (Axl^-/-) mice by uninephrectomy and DOCA-salt for 6 weeks. Controls were uninephrectomized and received tap water and regular chow ad libitum. DOCA-salt treatment increased systolic blood pressure by 25 mm Hg in both genotypes after 1 week. Systolic blood pressure remained significantly elevated in Axl^+/+ DOCA, whereas systolic blood pressure levels in Axl^-/- DOCA mice were the same as controls at 6 weeks. DOCA-salt increased relative kidney weight and glomerular hypertrophy by 40% compared with controls in both genotypes. Consistent with levels of systolic blood pressure, endothelium-dependent vasorelaxation was impaired in Axl^+/+ DOCA mice compared with Axl^+/+ controls, whereas in Axl^-/- DOCA mice relaxation responses were similar to Axl^-/- controls. In addition, endothelium-independent vasorelaxation was improved in Axl^-/- DOCA mice compared with Axl^+/+ DOCA mice. Nitrotyrosine and phospho-Akt immunoreactivity was significantly reduced in arteries from Axl^-/- DOCA mice compared with Axl^+/+ DOCA mice. The remodeling index of the mesenteric artery (media:lumen ratio) was significantly increased in Axl^+/+ DOCA mice compared with Axl^-/- DOCA mice. Finally, increased vascular apoptosis in the Axl^-/- DOCA mice suggests a likely mechanism for Axl-dependent effects on hypertension. These data strengthen the pathogenic role for Axl in salt-sensitive hypertension.