The chemopreventive effects of dietary n-3 PUFA in various pathologies has so far remained controversial, and we were interested in studying their potential influence on cell redox status. DHA (22:6n-3), a typical highly unsaturated n-3 PUFA, was used at 30µmol/l in a model of human fibroblast cell culture. A dose–response effect, roughly linear, was checked for DHA between 0 and 60µmol/l, and was accompanied by a large increase in intracellular GSH content. A time course study of this effect shows that, after a short fall, as soon as 4h after the beginning of the experiment, the large increase in the GSH content was associated with elevated catalytic activities of γ-glutamyl-cysteinyl ligase, glutathione reductase and glutathione S-transferase. This coordinated response is characteristic of an antioxidant response and was confirmed by the induction of expression of mRNA for γ-glutamyl-cysteinyl ligase, glutathione reductase and haem-oxygenase. This large increase in the GSH content contributes to decreasing the reactive oxygen species level, as assessed by the decreased accumulation of dichlorofluorescein inside cells. To our knowledge, this is the first report on a specific and potent effect of DHA for decreasing the oxidative stress of human fibroblasts.