NADPH dependent alkenal/one oxidoreductase (Aor) was discovered to be highly inducible in rat liver following treatment with the cancer chemopreventive agent 3H-1,2-dithiole-3-thione (D3T). Aor was further characterized as an Nrf2-regulated antioxidative enzyme that reduces carbon-carbon double bonds in a variety of , -unsaturated aldehydes and ketones. 15-Deoxy-delta^12,14-prostaglandin J₂ (15d-PGJ₂) is a reactive membrane lipid metabolite that activates multiple pathways including Nrf2-mediated induction of cytoprotective enzymes. Physiologically, it is postulated that 15d-PGJ₂ alkylates key regulatory proteins via the electrophilic carbon centers found in two , -unsaturated ketone moieties. This current study addresses the metabolism of 15d-PGJ₂ by rat Aor (rAor) and subsequent deactivation of the Nrf2 signaling pathway by both rat and human Aor. We demonstrate that induction of NADPH-dependent quinone oxidoreductase (Nqo1) activity by 15d-PGJ₂ is markedly attenuated in mouse embryonic fibroblasts that overexpress rAor. Luciferase reporter assay and quantitative real-time PCR confirmed these findings. Concentrations required for doubling the Nqo1 response are increased from 1.8 M in wild-type to >10 M in rat Aor transgenic fibroblasts. 15d-PGJ₂ is metabolized by recombinant rAor with a Km of 9.6 M and kcat of 18.5 min^-1. The major product is 12,13-dihydro-15-deoxy-delta^12,14-prostaglandin J₂ (dihydro-15d-PGJ₂). The reduction of C=C by Aor yielding dihydro-15d-PGJ₂ abolishes the inducer activity in an Nrf2 driven luciferase assay. Collectively, these results demonstrate that 15d-PGJ₂ can be catabolized by Aor thereby attenuating subsequent Nrf2 signaling and possibly inflammatory and apoptotic processes also influenced by 15d-PGJ₂.