Adiponectin circulates as trimer (LMW), hexamer (MMW) and high molecular weight multimer (HMW) but the distribution and effects of these isoforms have not been studied in detail. Monocytes were isolated from normal weight and overweight controls and patients with type 2 diabetes mellitus (T2D) and monocytic release of IL-6 positively correlated with the body mass index (BMI). HMW-adiponectin further enhanced and LMW-adiponectin reduced IL-6 release in monocytes. Systemic total adiponectin, and the HMW isoform were not different in these groups but MMW-adiponectin was lower in T2D, and LMW-adiponectin was reduced in the obese and T2D. Circulating LMW-adiponectin negatively correlated to monocytic IL-6 release. Systemic IL-6 was higher in the obese control group and T2D, respectively, but did not correlate with monocytic IL-6 secretion. Therefore, the current study indicates that HMW-adiponectin exerts pro- and LMW-adiponectin antiinflammatory effects and reduced LMW-adiponectin in obesity may partly contribute to elevated monocytic IL-6 release.