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Adiponectin exerts positive effects on metabolic and inflammatory processes. Adiponectin levels and some single-nucleotide polymorphisms (SNPs) seem to be associated with obesity. Here, we investigated the effects of a 4-week Hypocaloric diet and Physical exercise Program (HPP) on 268 young people with severe obesity. We evaluated the relationship between adiponectin levels and anthropometric and biochemical parameters, at baseline and after a 4-week HPP. Finally, we investigated some adiponectin gene variants and their correlation to biochemical parameters. Adiponectin levels were statistically lower in people with severe obesity than in controls. At the end of the HPP, all the people with severe obesity showed a Body Mass Index (BMI) reduction with a statistically significant increase in adiponectin levels. Genotyping, the adiponectin gene demonstrated a significant difference in 3 polymorphisms within the people with severe obesity. Besides, c.11377C&gt;G and c.11391G&gt;A homozygous subjects experienced more advantages by HPP. Furthermore, c.268G&gt;A heterozygous subjects showed an enhancement in lipid profile as well in adiponectin levels. The best predictor of the changes in adiponectin levels was represented by the c.268G&gt;A WT allele. Our study confirmed that a 4-weeks HPP in people with severe obesity results in metabolic amelioration associated with a significant increase of adiponectin levels. Importantly, we found that a specific genetic background in the <i>ADIPOQ</i> gene can predispose toward a more significant weight loss.