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Background: Fatty acids can modulate lipid metabolism, this is related to insulin resistance (IR). This study evaluated the relationship of plasma fatty acid profile with IR, fuel oxidative metabolism and plasma lipid concentration in 'healthy' women., Methods: Sixteen 'healthy', sedentary and non-obese women were evaluated under fasting conditions for fuel oxidation, plasma fatty acid profile, free fatty acids, triglycerides, glucose and insulin concentrations. IR, fuel oxidation and plasma lipids were measured under insulin-stimulated conditions. Using the Spearman test the correlation between relevant variables was assessed. Stepwise multiple regression analysis was done to identify the main clinical/metabolic and fatty acid determinants of IR., Results: Plasma arachidonic acid content (%) determined IR, and in combination with insulin-stimulated plasma triglyceride concentration explained 45% of the IR variance. IR was inversely related to physical fitness (rs = -0.48, p = 0.01). The latter was inversely associated to plasma saturated fatty acid content (%) (rs = -0.48, p < 0.01), but directly associated to plasma docosahexaenoic acid content (%) (rs = 0.40, p = 0.04)., Conclusions: Support for the hypothesis that specific fatty acids influence IR is provided. Plasma arachidonic acid was associated to IR, independent on clinical/metabolic study variables. Docosahexaenoic and saturated fatty acids could potentially affect insulin action through modulating mitochondrial oxidative function., ((c) 2007 S. Karger AG, Basel.)