Objective: Curcumin, principal curcuminoid in turmeric, is obtained from the rhizomes of Curcuma longa. This compound exhibits potent antioxidant, anti-inflammatory, immunomodulatory or anti-angiogenic properties. Several animal studies reported hypocholesterolemic, antioxidant, anti-atherogenic and antiplatelet activities of this compound, however the cardiovascular protective effect of curcumin was poorly investigated in humans. The aim of this study was to determine the effect of an acute intake of curcumin on vascular endothelial function in healthy smokers and its nutrigenomic impact in circulating immune cells. Methods: In a randomized, double-blind, cross-over study on 18 smokers (9 men and 9 women), 50–70 yrs old, the effect of curcumin (5 g) on gene expression in peripheral blood mononuclear cell (PBMC) and endothelial function was evaluated. Effect on expression of 93 genes involved in inflammation, cell adhesion, cholesterol absorption/efflux was assessed using TaqMan-Low-Density-Array (TLDA) and endothelial function was evaluated by Flow Mediated Dilatation (FMD). Measurements were done before and 2-hours after curcumin or placebo intake. Results: We failed to show significant difference between curcumin and placebo for FMD partly due to inter-individual variability. However, analysis of data separately for men and women revealed a significant effect of curcumin for FMD in women, but not in men. Similarly, no change in gene expression between curcumin and placebo was observed when data were analysed for all volunteers. However, analysis of gene expression data separately for men and women revealed 9 differentially expressed genes in men and 8 in women with 3 genes in common (FABP3, CXCL3, CCL20). Interestingly, the expression of the 9 and 8 genes was identified as up-regulated in men and down-regulated in women, respectively. Conclusion: Although results did not account for a beneficial effect of curcumin in the whole studied population, gender comparison analysis suggests a difference in nutrigenomic and vascular response to curcumin between men and women.