Coffee is widely consumed, especially during mental stress conditions. Cardiovascular impact of coffee remains debated because the underlying mechanisms of action are complex. We reported previously differential cardiovascular stimulation of coffee at rest depending on habitual consumption. The present study was designed to evaluate the effects of coffee on cardiovascular response to mental stress. In 15 healthy volunteers (6 habitual, 9 nonhabitual coffee drinkers), we assessed the effect of mental stress on blood pressure (BP), heart rate (HR), and muscle sympathetic activity (MSA) before and after a triple espresso, intravenous caffeine, and placebo in the same subjects. Under baseline conditions, mental stress significantly increases MSA (+2.5+/-0.7 volts per minute; +14.1+/-10.3%), systolic (+11.6+/-4.1 mm Hg) and diastolic BP (+6.4+/-2.0 mm Hg), and HR (+9.6+/-1.8 minutes(-1)). In nonhabitual coffee drinkers, a triple espresso but not caffeine induced an additional increase in systolic BP (+9+/-6.3 mm Hg; P=0.003) during mental stress, whereas in habitual drinkers, the stress-induced BP increase was blunted (+4+/-3.9 mm Hg; P=NS). As a result, nonhabitual coffee drinkers experienced significantly higher BP during mental stress than habitual drinkers (151+/-17.9/83+/-5.6 mm Hg versus 130+/-7.8/74+/-6.7 mm Hg; P<0.05). Caffeine induced similar effects in habitual and nonhabitual coffee drinkers at rest and during mental stress. The response to the cold pressor test was not influenced by coffee drinking in both groups. In conclusion, in nonhabitual coffee drinkers, coffee enhances the cardiovascular response to mental stress with an additional increase in systolic BP, whereas in habitual drinkers, the response is blunted. Caffeine alone does not exert any potentiating effect, confirming that ingredients other than caffeine are partially responsible for the stimulating effect of coffee on the cardiovascular system.