454 overweight/obese patients with knee OA were randomized to one of three interventions for the purpose of determining if any treatment was associated with significantly decreased the serum concentration of specific inflammatory biomarkers after 18 months: (1) Diet only, (2) Diet and Exercise, and (3) Exercise only intervention. Results demonstrated that a significant reduction of C1M and C3M were observed in the Diet only (D) and Diet and Exercise (D+E) groups when compared to the Exercise only (E) group. Additionally, significant decreases in C1M, C3M and CRPM were strongly associated with weight loss, and that significant changes in C3M and CRPM were associated with improvement in WOMAC function.