A fatty meal may represent a challenge of in vivo acute inflammatory reaction. We evaluated the acute effects of a standardised fatty meal administration on leukocytes and platelets and on their interactions on 61 subjects at different degree of cardiovascular risk, without any clinical event. Before and 2 hours after a fatty meal, blood cells were counted and markers of leukocyte (intracellular myeloperoxidase [MPO] and Mac-1) and platelet (P-selectin and microparticles) activation and mixed platelet-leukocyte conjugates measured by flow-cytometry. After the fatty meal, both white blood cell and platelet count significantly increased, more markedly in subjects with lower cardiovascular risk score. Mac-1 expression too increased (from 32.2 ± 27.2% to 45.6 ± 29.0%, p=0.0016), while MPO decreased (from 83.1 ± 16.3% to 64.5 ± 23.1%, p<0.0001). A trend for increased platelet activation and interaction with leukocytes was also observed. Women were more markedly susceptible to fatty meal challenge, as compared to men, while age did not seem to affect any cell response to fatty meal. Waist-to-hip ratio and body mass index influenced polymorphonuclear cells (PMN) degranulation and platelet count increase, respectively. Cellular responses to the fatty meal, in particular PMN degranulation, were attenuated in subjects at higher degree of cardiovascular risk, who showed a basal mild inflammatory activation status. In conclusion, a fatty meal consumption may represent a model of acute inflammatory response and appears to be modulated by different demographic and cardiovascular risk degree. This model could be applied to study the effect of food-derived antioxidants or nutritional supplements, but its relevance remains to be demonstrated.