ABSTRACT Background: Obesity is now considered a low grade, chronic inflammatory disease that is associated with metabolic disorders like type 2 diabetes and insulin resistance. Weight loss in obese and overweight subjects, achieved both by energy-restricted diet or surgery, was found to be a critical factor for reducing the level of inflammatory markers. Objective: To find if the effect of weight loss on inflammatory mediators in overweight and obese patients will be affected by the presence or absence of metabolic syndrome (MetS). Methods: The final patient sample was (114) patients. According to BMI and presence or absence of MetS, they were divided into 4 groups: Group (1): overweight with MetS. Group (2): overweight without MetS. Group (3): obese with MetS. Group (4): obese without MetS. An eight-week program for weight reduction including dietary restrictions and physical activity was followed by all patients. Obesity parameters and inflammatory mediators were measured before and after weight reduction. Results: Adiponectin, TNFα and IL6 (the significantly different inflammatory mediators before the weight loss program) showed that the highest degree of significant difference was in TNFα between group 2 and 4. Delta change showed that after the weight loss program the changes were significant between the four groups in CRP, TNFα, and IL6. Group 2 and 3 were the only two groups showing significant difference in the 3 parameters. Conclusions: Presence of MetS augments the beneficial effect of weight loss in those patients in comparison to patients who lack the criteria of MetS. Keywords: Weight reduction; Inflammatory mediators; Metabolic syndrome.