Background: Obesity is a major contributor to preventable disease and death across the globe. Obesity is complex. Although its risk factors are myriad and compounding, there is an urgent need for a deeper understanding of the way risk factors interact with each other. Leptin is a peptide regulates food intake and body weight. However, the notion of leptin as an anti-obesity hormone was called into question because obesity is typically associated with high leptin levels and not leptin deficiency thus, we aimed to measure leptin levels in obese female in correlation to anthropometric measures and to evaluate the impact of weight loss on its level and metabolic parameters. Subject and methods: case-control study enrolled 40 control groups, 50 obese women. We measured anthropometric measures BMI, Waist/hip ratio (WHR). Fat mass index (FMI%) and free fat mass index (FFMI%) were assessed by dual energy X-Ray absorptiometry (DEXA) The serum levels of leptin were measured by ELISA. Results: Our results revealed that serum leptin levels were higher in obese women compared to controls. Moreover, it was positively correlated to anthropometric measures, glycemic and lipid profile. Linear regression analysis revealed that BMI was the main independent studied parameters associated with serum leptin level among other clinical and laboratory biomarkers. Interestingly, after 12 weeks of following the Mediterranean diet (MD) based weight loss program, serum leptin levels were decreased. Logistic regression analysis was performed to detect the main predictors' biomarkers associated with weight loss among obese women. We found that serum leptin and FMI% were an independent predictor of response with odds ratios of 1.69 and 1.64 respectively (P < 0.001), Receiver operating characteristic analyses revealed that the AUC of serum leptin in discriminating obese women from lean ones was 0.893 (95% CI ¼ 0.815e0.917) with sensitivity ¼ 90%, specificity ¼ 96%, and the cutoff values was 36.32 ng/ml. Conclusion: Serum leptin could be a valuable diagnostic marker of obesity and its comorbidities. Moreover, significant weight loss leads to decrease serum leptin levels and improvement of glycemic and lipid profiles.