The connection between caffeine and its potentially detrimental effects on blood markers of cardiovascular disease (CVD) are controversial. Most studies have focused on cholesterol as a putative mediator of the caffeine–CVD relationship. Other blood markers such as C-reactive protein (CRP) and fibrinogen have been understudied. We examined the effects of caffeine and psychological stress on these CVD markers in healthy, young men and women with a confirmed family history of hypertension. A total of 52 normotensive, healthy adults (26 men and 26 women) aged 18–29 years (21.4 ± 0.3) participated in a laboratory session to examine stress reactivity following caffeine consumption. All participants had normal cholesterol levels. Blood pressure (BP), heart rate, serum cortisol and CRP and plasma fibrinogen were collected. Men and women administered caffeine displayed an additional increase in systolic BP and cortisol response to the stressor (p < 0.05). Stress interacted with caffeine and sex to alter cortisol, fibrinogen and systolic BP but not CRP levels. These results may shed light on sex-specific pathways that associate caffeine with CVD. Copyright © 2013 John Wiley & Sons, Ltd.