Compared with saturated fat, n-3 long-chain PUFA-rich fish oil improves insulin sensitivity in rats. We studied whether n-3 long-chain PUFA could prevent insulin resistance induced by dexamethasone (a glucocorticoid) in healthy human volunteers. A group of eight subjects was studied twice after a 2 d dexamethasone treatment, before and after a 3-week supplementation with fish oil (providing daily doses of 1.1 g 20 : 5n-3 and 0.7 g 22 : 6n-3). The subjects were studied during the basal state and over the 6 h following an oral glucose load (1 g/kg). Plasma glucose fluxes were traced with [6,6-2H2]glucose and [13C]glucose (naturally 13C-enriched corn glucose). Substrate oxidation was obtained from indirect calorimetry. Following fish oil supplementation, plasma glucose fluxes and substrate oxidation were maintained despite a 17 % reduction (P<0.05) in the area under the curve of plasma insulin response, suggesting an insulin-sensitizing effect.