Experimental and epidemiological studies have demonstrated the beneficial effects of the traditional Mediterranean diet (TMD) on the incidence and progression of atherosclerosis. Several genes play a major role in determining atherosclerosis susceptibility. We compared the short-term effects of two TMD diets versus a control diet on the expression of pro-atherogenic genes. One TMD diet was supplemented with virgin olive oil (VOO) (TMD+VOO) and the other with nuts (TMD+nuts). Gene expression was analyzed in monocytes from 49 asymptomatic high cardiovascular-risk participants (23 men, 26 women), aged 55-80 years. Monocytes were isolated from blood before and 3 months after dietary intervention. We analyzed the expression of genes involved in inflammation [cyclooxygenase-1 (COX-1), cyclooxygenase-2 (COX-2) and monocyte chemoattractant protein (MCP-1)], genes involved in foam cell formation [low-density lipoprotein receptor-related protein (LRP1), LDL receptor and CD36], and genes involved in thrombosis [tissue factor (TF) and tissue factor pathway inhibitor (TFPI)]. We found that TMD+VOO intervention prevented an increase in COX-2 and LRP1, and reduced MCP-1 expression compared to TMD+nuts or control diet interventions. TMD+nuts specifically increased the expression of CD36 and TFPI compared to TMD+VOO and control diet intervention. Our findings showed that the Mediterranean diet influences expression of key genes involved in vascular inflammation, foam cell formation and thrombosis. Dietary intervention can thus actively modulate the expression of pro-atherothrombotic genes even in a high-risk population.