The objective was to explore the relationship between the cortisol awakening response (CAR) and the metabolic syndrome (MetS) as defined by the National Cholesterol Education Program criteria. The final study sample consisted of 91 women (14 with MetS) and 84 men (15 with MetS), aged 45 to 70 years, from a general population sample. The only exclusion criteria were no consent, pregnancy, or insufficient cortisol testing. On the day of measurement (weekday), salivary cortisol was sampled at awakening and 15 minutes after awakening. Relative CAR (CAR%) and the MetS were the main variables studied. Results showed that, in women with the MetS, cortisol at awakening was significantly lower (mean, 8.92 vs 12.33 nmol/L; P = .05) and the CAR was significantly higher (91.4% vs 36.5%, P < .001) than in women without the syndrome. Significant difference in the relative CAR was also present between men and women with MetS (38.5% and 91.4%, respectively; P = .02). No difference was seen in the awakening response comparing men with and without the MetS. In a regression model, the response to awakening was dependent on the MetS in women (F(1,89) = 13.19, P < .001); but the model was not significant in men. Furthermore, the awakening response was associated with more depressive symptoms in women (F(1,80) = 8.12, P = .01) and with weekday/weekend cortisol sampling in men (F(1,82) = 4.63, P = .03). The association between the relative CAR and the MetS remained significant but somewhat attenuated after adjusting for depressive symptoms (P = .01). Results indicate a sex difference in the CAR% in the presence of the MetS independent of depressive symptoms, a known correlate of the MetS.