Summary. Background: Obesity is associated with an increased atherothrombotic morbidity/mortality risk. However, there is no direct evidence of subclinical activation of the endothelium in obese subjects without other major cardiometabolic risk factors. Objectives: We applied a translational approach to investigate endothelial activation occurring in response to the components secreted by visceral and subcutaneous adipose tissue and their corresponding cell fractions obtained from obese subjects without other major cardiometabolic risk factors, as compared with non-obese controls. Methods: Fat pads and cell fractions were incubated with serum-free medium to obtain their secretomes, which were analyzed by protein arrays. Endothelial cells (ECs) were exposed to the different secretomes to evaluate changes in gene expression, composition and reactivity of the extracellular matrix (ECM), and cell growth and viability. Results: ECs incubated in the presence of obese secretomes displayed increased proliferation, altered cell morphology, augmented expression of VCAM-1, ICAM-1, and von Willebrand factor, and higher ECM reactivity towards circulating platelets. The visceral secretomes, especially the stromal one, induced the strongest expression of these markers, together with a more reactive ECM. These changes occurred through nuclear factor-κB (NF-κB) activation. Conclusion: This is the first translational study demonstrating that the cytokines secreted by the adipose tissue from obese individuals without other major cardiometabolic complications have a hazardous effect on the endothelium, through activation of the NF-κB pathway.