Accumulating evidence indicates that maternal high fat diet (HFD) is associated with metabolic syndrome and cardiovascular disease in adult offspring. The present study tested the hypothesis that maternal HFD modulates the brain renin-angiotensin system (RAS), oxidative stress and proinflammatory cytokines that alter angiotensin II and tumor necrosis factor-α (TNF-α) actions and sensitize the angiotensin II-elicited hypertensive response in adult offspring. All offspring were cross-fostered by dams on the same or opposite diet to yield 4 groups: offspring from normal fat control diet (CD)-fed dams suckled by CD-fed dams (OCC) or by HFD-fed dams (OCH), and offspring from HFD-fed dams fed HFD suckled by CD-fed dams (OHC) or by HFD-fed dams (OHH). RT-PCR analyses of the lamina terminalis (LT) and paraventricular nucleus (PVN) indicated upregulation of mRNA expression of several RAS components, NADPH oxidase and proinflammatory cytokines in 10-week old male offspring of dams with HFD during either pregnancy, lactation or both (OHC, OCH and OHH). These offspring also showed decreased cardiac baroreflex sensitivity and increased pressor responses to intracerebroventricular microinjection of either angiotensin II or TNF-α. Furthermore, chronic systemic infusion of angiotensin II resulted in enhanced upregulation of mRNA expression of RAS components, NADPH oxidase and proinflammatory cytokines in the LT and PVN and an augmented hypertensive response in the OHC, OCH and OHH groups when compared to the OCC. The results suggest that maternal HFD blunts cardiac baroreflex function and enhances pressor responses to angiotensin II or proinflammatory cytokines through upregulation of the brain RAS, oxidative stress and inflammation.