OBJECTIVES: We investigated the acute and chronic combined effect of cigarette smoking and caffeine intake on aortic stiffness and wave reflections. BACKGROUND: We have shown that smoking and caffeine separately increase arterial stiffness. Aortic stiffness and wave reflections are important determinants of the efficient performance of the cardiovascular system and prognosticators of cardiovascular risk. METHODS: The acute effects of smoking (one cigarette), caffeine (200 mg, equivalent to 2 cups of coffee), and smoking plus caffeine were studied in 24 healthy subjects according to a randomized, placebo- and sham procedure-controlled crossover design. The chronic effect of smoking and caffeine was studied in a population study that enrolled 160 healthy subjects. RESULTS: Acute study: there was a significant interaction between caffeine and smoking with regard to pulse-wave velocity (p < 0.01) and augmentation index (p < 0.05). When smoking followed caffeine intake, pulse-wave velocity and augmentation index increased further by 0.52 m/s and 13.4%, respectively, reaching a total of 0.85 m/s and 17.4%, 0.17 m/s and 9.2% in excess of the mere sum of caffeine effect (0.33 m/s and 4%) alone and smoking effect alone (0.35 m/s and 4.2%). Population study: there was a significant interaction of chronic coffee consumption and smoking regarding pulse-wave velocity (p < 0.05) and augmentation index (p = 0.001). CONCLUSIONS: The present study shows, for the first time, that when smoking and caffeine intake are combined, they interact and exert a synergistic, unfavorable effect on aortic stiffness and wave reflections on both an acute and chronic basis.