Background and aims Obesity is associated with an increased risk of developing atherosclerosis. Interleukin-20 (IL-20) is a pleiotropic cytokine thought to be involved in the onset and progression of atherosclerosis. The aim of this study was to determine whether circulating levels of IL-20 are elevated in obese women and whether they could be affected by a substantial decrease in body weight. Methods and results Fifty obese and 50 age-matched, normal weight, premenopausal women participated in the study. Obese women entered into a medically supervised weight loss program aimed at reducing body weight to 90% of baseline. We measured anthropometric, glucose and lipid parameters, and IL-20, C-Reactive Protein (CRP) and interleukin-10 (IL-10) circulating levels. Circulating IL-20 and CRP levels were significantly higher in obese than control women (P = 0.01), while IL-10 levels were significantly lower; IL-20 levels were positively associated with body weight (r = 0.35; P = 0.02) and visceral fat (waist–hip ratio; r = 0.32; P = 0.025). Caloric restriction-induced weight loss (>10% of original weight) over 6 months reduced IL-20 levels from 152 (112/184) to 134 (125/153) pg/ml (median and 25%/75%; P = 0.03), and it was positively associated with changes in body mass index and waist–hip ratio. Conclusion In premenopausal obese women, IL-20 levels are higher than matched normal weight control women, are associated with body weight and waist–hip ratio, and are reduced by weight loss.