Abdominal fat-related activation of the innate immune system and insulin resistance (IR) are implicated in the pathogenesis of cardiovascular diseases. Recent data support an important role of the adaptive immune system as well. In this study, we investigate the association between waist circumference and markers of systemic adaptive immune activation, and the potential mediating role of innate immune activation and/or IR herein. The study population consisted of 477 (304 men) individuals (mean age: 59.4±7.0 years) in whom waist circumference, HOMA2-IR (IR derived from homeostasis model assessment), and markers of innate (C-reactive protein (CRP), interleukin (IL)-6, serum amyloid A (SAA)) and adaptive (neopterin, soluble CD25 (sCD25)) immune activation were measured. These markers were compiled into an adaptive and innate immune activation score by averaging the respective z-scores. After adjustments for age, sex, glucose metabolism, smoking status, prior cardiovascular disease, and other risk factors, waist circumference was associated with the adaptive (standardized regression coefficient Β = 0.12 (95% confidence intervals: 0.04-0.20)) and the innate immune activation scores (Β = 0.24 (0.17-0.31)), and with HOMA2-IR (Β = 0.49 (0.42-0.56)). The innate immune activation score and HOMA2-IR were also positively associated with the adaptive immune activation score (Β = 0.31 (0.21-0.40) and Β = 0.11 (0.02-0.21), respectively). The association between waist circumference and the adaptive immune activation score was completely abolished when further adjusted for innate immune activation and HOMA2-IR (to Β = 0.01 (0.10-0.08)), and the specific mediation effects attributable to each of these variables were 58% and 42%, respectively. We conclude that abdominal obesity is associated with systemic adaptive immune activation and that innate immune activation and IR constitute independent and equally important pathways explaining this association. 2011 The Obesity Society.