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T cell derived cytokines, interleukin 17A (IL17A) and interferon gamma (IFNg), promote angiotensin II (Ang II)-induced hypertension and end-organ damage. Interleukin 21 (IL21), produced primarily by T follicular helper (Tfh) cells, has been shown to induce IL17A and IFNγ production from T effector cells. IL21 is also a potent activator of germinal center (GC) B cells and immunoglobulin (Ig) class switching. We hypothesized that IL21 plays a fundamental role in hypertension and hypertensive end-organ damage through its effects on pro-inflammatory T cell polarization, vascular dysfunction, and enhanced Ig secretion. CD4+ T cells from Ang II infused WT mice exhibit 1.5-fold increased IL21 mRNA expression and 2-fold increased IL-21 production compared to vehicle. We found IL21 -/- mice exhibit a 30mmHg reduction in systolic blood pressure (SBP) in response to 4 weeks of Ang II infusion compared to age-matched wild type (WT) mice. Further, IFNg and IL17A production from CD8+ or CD4+ T cells, respectively, was abrogated in IL21 -/- mice vs. WT mice infused with Ang II. We also found Tfh cells and GC B cells significantly increased in the aortas and mesenteric vessels of Ang II WT mice but not IL21 -/- mice. Ang II induced an increase in percent of lymph node GC B cells and IgG/IgM ratio, consistent with Ig class switching. Ang II-induced increase in renal injury was also blunted in IL21 -/- mice vs. WT mice. Mesenteric vessels from IL21 -/- mice were protected from Ang II-induced endothelial dysfunction. IL21 -/- mice also developed blunted aortic fibrosis and reduced smooth muscle cell hypertrophy after 4 weeks of Ang II vs. WT mice. IL-21 neutralization beginning 2 weeks after Ang II resulted in a 15 mmHg reduction in SBP and reversal of aortic inflammation and vascular endothelial dysfunction compared to isotype control treated animals. Lastly, CD4+ T cell production of IL21 positively correlated with SBP in human volunteers, and in fact, IL-21 production was significantly higher in hypertensive compared to normotensive subjects. Taken together, these studies provide compelling evidence that IL21 may function as a master cytokine in the pathogenesis of hypertension and suggest that therapies targeting IL21 may reduce hypertension and the associated end-organ damage.