The immune system plays a major role in animal models of hypertension (HTN) and end-organ damage. However, few studies have assessed the role of lymphoid organs in the pathogenesis of HTN. We have shown previously that prior splenectomy (SPLX) significantly alters tissue inflammation; however the effect of SPLX on HTN remains unclear. Therefore, the objective of the current study is to determine whether prior SPLX influences the development of HTN in 2 different mouse models. Mice underwent SPLX or sham surgery 7 days prior to the induction of HTN using angiotensin-II (AngII, 400ng/kg*min s.c.) or nitric oxide synthase inhibition using L-NAME (30mg/kg*d in drinking water). Systolic blood pressure (SBP) was measured by tail-cuff manometer daily and mice were euthanized 14 days after induction of HTN. Heart weight/body weight (H/BW) ratios were calculated and kidney leukocyte infiltration was analyzed by flow cytometry. Mice with prior SPLX+AngII had significantly lower (P=0.03) SBP at both week 1 (148±7) and week 2 (135±7) as compared to Sham+AngII (174 and 173±7mmHg, n=5). Similarly, SPLX+AngII mice had significantly smaller (P=0.007) H/BW (4.3±0.3) as compared to Sham+AngII treated mice (5.2±0.4mg/g BW). Interestingly, no difference was observed in renal CD45+ (9.8±3 vs 10.6±3x105 cells/g, P=0.64) or CD3+ T-cell infiltration (8.8±0.2 vs 9.6±0.1x104 cells/g , P=0.64) between the Sham+AngII and SPLX+AngII treated mice, respectively (n=4/5). Furthermore, SPLX did not appear to influence the development of L-NAME HTN. SPLX+L-NAME mice had similar (P=0.84) SBP (145±4mmHg) as the Sham+L-NAME group (146±4mmHg, n=6) after 2 weeks. Relative heart weights were also similar (P=0.45) between SPLX+L-NAME (4.9±0.2) and Sham+L-NAME treated mice (4.8±0.3mg/g BW). Our data suggests that the full pressor response to AngII is dependent on the spleen. However, the effect of the spleen appears to be independent of renal inflammation. Moreover, the protective effect of the spleen is specific to AngII-dependent HTN and does not appear to be generalizable to all mouse models of hypertension. Further studies are needed to understand the physiological link between lymphoid organs (such as the spleen), renal inflammation, and the development of chronic HTN.