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Abstract: Background: Both inflammation and immunity are involved in the development and progression of atherosclerosis. Obesity is considered a major modifiable cardiovascular risk factor, however, the correlation between increasing degrees of obesity and cardiovascular risk is not clear yet. Aim of our study was to investigate how different degrees of obesity are associated with inflammation and immune system responses. Methods: One-hundred healthy individuals were divided into 3 groups according to body mass index (BMI): 22 overweight (OW), 26 obese (O) and 52 morbidly obese (MO). High-sensitivity C-Reactive Protein (hs-CRP, immunonephelometry), leptin (radio-immunoassay) and CD4+CD28nullT-lymphocytes (flow-cytometry), a particular subset of T-lymphocytes with pro-atherogenic and plaque-destabilizing properties, were assessed. Results: hs-CRP levels were significantly higher in O vs OW (p=0.036), in MO vs OW (p<0.001) and in MO vs O (p=0.012). Similarly, leptin levels were higher in O vs OW (p=0.02), in MO vs OW (p<0.001) and in MO vs O (p<0.001). CD4+CD28nullT-lymphocytes were higher in O vs OW (p<0.001), in O vs MO (p=0.03) and in MO vs OW (p=0.01). hs-CRP and leptin levels significantly correlated each other (r=0.39; p<0.001) and with waist circumference (r=0.52; p<0.001; r=0.64; p<0.001) and BMI (r=0.60; p<0.001; r=0.74; p<0.001). Conclusions: Our study demonstrates that, notwithstanding higher levels of inflammation, MO are characterized by less detrimental immune activation, as shown by the reduced CD4+CD28nullT-cells expansion as compared to OW and O, which might translate in less immune vascular injury. These findings suggest that MO might represent a particular population, in which different pathophysiological mechanisms take part if compared with “classic” obesity. [Copyright &y& Elsevier]