Background. Adiponectin (APN) possesses anti-inflammatory and antiatherogenic effects. Atrial fibrillation (AF) is burdened by enhanced systemic inflammation and platelet activation, as documented by increased blood levels of soluble CD40L (sCD40L). The interplay between APN and platelet activation in AF is still undefined. Materials and Methods. Circulating levels of APN and sCD40L were measured in 257 anticoagulated nonvalvular AF patients. Exclusion criteria were as follows: prosthetic heart valves, cardiac revascularization in the previous year, severe cognitive impairment, chronic infectious or autoimmune diseases, and active cancer. Results. Mean age was 72.9 (±8.7) years and 41.6% were female. Serum APN and plasmatic sCD40L were inversely correlated (R −0.626, P