We recently showed that α-, γ-, and δ-tocopherols (Toc) were isoform dependent in modulating an inflammatory response in differentiated human Caco-2 intestinal cells. Here, we aim to investigate the relative capacity of Toc isoforms to modify the stress-activated NfκB and Nrf-2 signaling pathways that regulate the expression of pro-inflammatory cytokines and antioxidant enzymes, respectively, in this well-established in vitro model of the small intestine The modulation of IFNγ/phorbol myristate acetate (PMA)-induced inflammatory responses, determined by the expression of IL8 mRNA and protein, corresponded to the extent by which different Toc isoforms altered intracellular oxidative status in Caco-2 cells. α Toc was more effective at suppressing IFNγ/PMA-induced NfκB activation than γ-Toc, while δ-Toc was ineffective. On the other hand, only δ-Toc and to a lesser extent γ-Toc promoted IFNγ/PMA-induced Nrf-2 activation. Up-regulation of Nrf-2 by δ-Toc coincided with a decrease in GSH/GSSG ratio, thus pointing to pro-oxidant activity of δ-Toc isoform in IFNγ/PMA-stimulated Caco-2 cells. The induction of oxidative stress in IFNγ/PMA-treated cells by δ-Toc was lowered (P < 0.05) in the presence of ascorbic acid. Ascorbic acid also enabled a greater suppression of IL8 secretion than when cells were treated with δ-Toc isoform alone. Our findings show that δ-Toc uniquely promoted oxidative stress which translated to Toc isoform-specific modulation of the stress-activated Nrf-2 and NfκB signaling pathway and an influence on IL8 expression.