Knockout (KO) of IL-6 has been shown to attenuate angiotensin II (AngII) hypertension, and mineralocorticoid receptors (MR) have been reported to contribute to the increase in IL-6 during acute AngII infusion. This study determined whether that MR action is sustained with chronic AngII infusion and plays a role in mediating AngII hypertension. AngII infusion (90 ng/min) increased plasma IL-6 from 1.6±0.6 to 22.7±2.2 and 19.9±3.2 pg/ml on days 7 and 14, respectively, and chronic MR blockade with spironolactone attenuated that only at day 7 (7.2±2.2 pg/ml). AngII increased MAP (19 hrs/day with telemetry) approximately 40 mmHg, but in AngII+spironolactone mice (25 or 50 mg/kg/day) MAP was not significantly different despite a tendency for lower pressure the first 6 days. To isolate further the mineralocorticoid link to IL-6 and blood pressure, DOCA-salt hypertension was induced in IL-6 KO and wild type (WT) mice. Plasma IL-6 increased from 4.1±1.7 to 34.5±7.0 pg/ml by day 7 of DOCA treatment in the WT mice, but was back to control levels by day 14. An IL-6 bioassay using the murine B9, B-cell hybridoma cell line demonstrated that plasma IL-6 measurements reflected actual IL-6 bioactivity. The hypertension was not different and virtually superimposable in WT vs. IL-6KO mice, averaging 145±2 and 144±3 mmHg, respectively. Both experiments confirm chronic stimulation of IL-6 by mineralocorticoids, but show that it is transient. In addition, IL-6 was not required for mineralocorticoid hypertension. This suggests that aldosterone contributes to the increase in plasma IL-6 in the early stage of AngII hypertension, but that the blood pressure actions of IL-6 in that model are linked most likely to AngII rather than aldosterone.