Human immunodeficiency virus (HIV)‐induced inflammation, and its consequences within the central nervous system (CNS), must be countered by multiple pharmacologic agents, and 15‐deoxy‐Δ12,14‐prostaglandin J2 (15d‐PGJ2) may hold promise in the treatment of pathologies associated with this inflammatory response. 15d‐PGJ2 can repress the inflammatory response by means of peroxisome proliferator‐activated receptor‐γ (PPARγ)‐dependent and ‐independent mechanisms. However, its precise role and antiinflammatory mechanism in the hippocampus remain poorly understood. In the present study, rat hippocampal slices were stimulated with full‐length HIV‐1 Tat protein to investigate the role of 15d‐PGJ2 8in the hippocampal inflammatory response. Pretreatment of slices with 15d‐PGJ2 markedly reduced Tat‐induced monocyte chemoattractant protein‐1 (MCP‐1/CCL2) production. Interestingly, the PPARγ antagonist GW9662 did not inhibit action of 15d‐PGJ2, confirming the latter's PPARγ‐independent mechanism of mediating antiinflammatory effects. Despite 15d‐PGJ2's increasing the expression of heme oxygenase‐1 (HO‐1), its action was not abrogated by the HO‐1 inhibitor zinc protoporphyrin IX (ZnPPIX), nor was it recapitulated by HO‐1 inducers such as cobalt protoporphyrin (CoPP). Moreover, short interfering RNA (siRNA)‐directed knockdown of HO‐1 did not abolish the antiinflammatory action of 15d‐PGJ2 against Tat‐induced MCP‐1 production in human microglia‐like THP‐1 cells. Conversely, 15d‐PGJ2 suppressed Tat‐induced ERK1/2 activation, decreasing MCP‐1 production upon Tat stimulation. The NADPH oxidase inhibitors DPI and apocynin also abrogated Tat‐stimulated ERK1/2 activation, reducing MCP‐1 production. Collectively, these data demonstrate that the antiinflammatory effects of 15d‐PGJ2 on the hippocampus are exerted through inhibition of Tat‐mediated ERK1/2 activation, coupled with that of a redox‐sensitive pathway, independent of PPARγ and HO‐1. © 2012 Wiley Periodicals, Inc.