BACKGROUND AND AIMS: Omentin-1 might play a role in insulin resistance and obesity. This study is aimed at evaluating the influence of weight loss treatment on omentin-1 concentrations and other parameters after 2 different hypocaloric diets in obese subjects. METHODS: A total of 239 obese subjects were randomly allocated during 12 weeks (Diet I - high-fat diet vs. Diet II - low fat diet), and their anthropometric and biochemical status were evaluated. RESULTS: After dietary intervention, BMI, weight, fat mass, waist circumference, systolic blood, triglycerides, LDL cholesterol, insulin levels and homeostasis model assessment for insulin resistance decreased in a statistical manner from their base values. After consuming diet II (low fat diet), the omentin-1 levels increased in males (20 ± 14 ng/mL) and females (35 ± 19 ng/mL). No changes were observed in omentin-1 levels after consuming hypocaloric diet type I (high fat). The multiple regression analyses after weight loss with diet I adjusted by age and sex showed a statistical association between BMI kg/m2 (Beta -0.33: 95% CI -4.58 to -0.11) and post-treatment omentin-1 levels. The analysis after weight loss with diet II showed a statistical association with BMI kg/m2 (Beta -0.31: 95% CI -3.93 to -0.08) and insulin UI/L (Beta -0.25: 95% CI -4.63 to -0.05) with post-treatment omentin-1 levels. CONCLUSIONS: Our design showed a significant increase in serum omentin-1 levels after weight loss secondary to a low fat hypocaloric diet, in contrast to no changes following consuming a high fat hypocaloric diet.