Objective The recently discovered peptide irisin has been hypothesized to be a regulator of body metabolism. The objective of this work was to evaluate whether circulating human irisin levels are modulated by body size and changes in adiposity during an energy restriction treatment and the subsequent weight regain. Methods A group of 94 obese patients (50 men, 44 women; 49.4 ± 9.4 years; BMI 35.6 ± 4.5 kg/m2) participated in a weight loss program following an 8‐week hypocaloric diet (−30% energy expenditure) with a weight maintenance follow‐up. The patients were evaluated at 0, 8, and 24 weeks after starting treatment. In addition, 48 normal‐weight subjects (16 men, 32 women; 35.71 ± 8.8 years; BMI 22.9 ± 2.2 kg/m2) participated as controls. Plasma irisin, body weight, body composition, and hormones controlling energy homeostasis were measured. Results Irisin levels were higher in obese subjects (353.1 ± 18.6 ng/mL) than in those of normal‐weight (198.4 ± 7.8 ng/mL; P ≤ 0.001) and were also higher in men (340.9 ± 20 ng/mL) than in women (267.6 ± 12 ng/mL; P < 0.05). Moreover, irisin plasma levels were significantly correlated with high levels of direct and indirect adiposity markers, such as weight, BMI, waist circumference, and fat mass, as measured by bioimpedance, but not with height or leptin levels. Interestingly, irisin levels paralleled body weight reduction after the dietary treatment (week 8) and again returned to the baseline levels at 24 weeks in those patients regaining the lost weight. Conclusions Irisin strongly reflects body fat mass, suggesting that the irisin circulating levels are conditioned by adiposity level. Am. J. Hum. Biol. 26:198–207, 2014. © 2013 Wiley Periodicals, Inc.