Technical Abstract: Some studies have shown that acute intake of high-phenol virgin olive oil reduces pro-inflammatory, pro-oxidant and pro-thrombotic states, but it remains unclear if the effects attributed to its phenolic fraction are exerted at the transcriptional level in vivo. Gene expression microarray analysis was performed on peripheral blood mononuclear cells at the postprandial period. Two virgin olive oil-based breakfasts with high (398 ppm) and low (70 ppm) content of phenolic compounds were administered to twenty patients with metabolic syndrome following a double-blinded random crossover design. Microarray analysis identified 98 differentially expressed genes (79 underexpressed and 19 overexpressed) when comparing the acute intake of phenol-rich olive oil with the low-phenol olive oil. Many of those genes have been linked recently, through GWA studies and animal models, to obesity, dyslipidemia, type 2 diabetes mellitus and coronary disease. Among these, several genes are involved in inflammatory processes mediated by transcription factor NFkappa B, jun N-terminal kinase JNK, activator protein-1 transcription factor complex AP-1, cytokines, mitogen-activated protein kinases MAPKs or arachidonic acid pathways. In conclusion, part of the beneficial effects of a virgin olive oil phenolic fraction could be exerted by modulating the expression of pro-inflammatory genes.