Systemic hyperosmotic stimulation (HS) evokes increases in sympathetic nerve activity (SNA) mediated by activation of angiotensin II type 1 (AT1) receptors in the hypothalamic paraventricular nucleus(PVN), as described by Chen and Toney (2001). Recently, macrophage inhibitory migration factor (MIF) can antagonize the hypertension evoked by angiotensin II acting at the level of the PVN (Li et al, 2006). This inhibitory effect of MIF is due to its intrinsic thiol-protein oxidoredutase (TPOR) activity (Sun et al, 2007). In this study, we evaluated the effect of virally mediated over expression of either MIF or C60SMIF (which lacks TPOR activity) in the PVN on the sympathoexcitation induced by hyperosmolality (HS). Under deep halothane anaesthesia, male Wistar rats (65-85 g) were decorticated to make insentient and perfused intra-arterially (Antunes et al. 2006). HS was induced by raising perfusate osmolality from 290 to 380 mOsmol for 40 s. Adeno associated viruses employed for over expression of MIF (1.0x 10⁸), C60SMIF (1.0x 10⁸) or eGFP (8.3 x 10⁸) were injected bilaterally (500 nl/side) into the PVN as was saline as a control. Seven to 10 days later the HS-induced sympathoexcitation in both the saline and eGFP groups (increases of 27 ± 4% and 25 ± 4%, respectively) was not observed in the MIF group (4 ± 5%). Conversely, the HS induced SNA response was potentiated (45 ± 6%) in the C60SMIF group. When MIF injections were located outside the PVN a response similar to control was observed. Imunohistochemical analysis demonstrated that MIF expression in PVN was restricted to neurones some of which were immunopositive for vasopressin. We propose that MIF acting within the PVN is a major counter regulator of HS induced sympathoexcitation, which is dependent on its TPOR activity. Further, enhancing TPOR activity may have therapeutic potential in restricting salt-induced hypertension.