Background. For the metabolically healthy obese (MHO) subjects, it is unclear whether weight loss provides cardiometabolic benefits. Our objective was to evaluate whether changes in adipokine and inflammatory biomarker levels were related to lifestyle modification (with Mediterranean diet and physical exercise program). Methods. 115 women (35-55 years) with BMI of 30-40 kg/m² and ≤1 metabolic syndrome criteria were included. After a 2-year intervention, participants were classified by percent weight loss: Group 1, <5%; Group 2, ≥5%-<10%; and Group 3, ≥10%. Anthropometric data, inflammatory biomarker (IL-6, TNFa, and hsCRP) and adipokine levels (adiponectin and resistin), and lifestyle program adherence at baseline and 2 years were analyzed. Results. The final sample comprised 67 women. 23 (38.3%) lost <5%, 22 (36.7%) lost ≥5%-<10%, and 22 (36.7%) lost ≥10% of baseline weight. After 2 years, in Group 1, adiponectin, hsCRP, IL-6, and TNFa decreased (-1.2 ng/ml, p=0.003; -2.1 mg/l, p=0.003; -2.4 pg/ml, p<0.001; and -2.4 pg/ml, p=0.001, respectively) and resistin increased (+2.4 ng/ml, p<0.001). In Group 2, hsCRP and IL-6 decreased (-2.0 mg/l, p=0.009 and -2.6 pg/ml, p=0.001) but TNFa increased (+0.2 pg/ml, p=0.02). In Group 3, resistin increased (+3.5 ng/ml, p<0.001) but hsCRP, IL-6, and TNFa decreased (-2.0 mg/l, p=0.009; -2.5 pg/ml, p<0.001; and -4.1 pg/ml, p<0.001). Adiponectin, hsCRP, and physical exercise correlated significantly to subjects’ dietary adherence. Conclusion. Weight loss reduces inflammatory biomarkers in the MHO but induces a deterioration in the adipokine profile, which does not improve with diet and exercise intervention. These findings allow us to clarify mechanisms behind inflammation and metabolic disorder genesis so as to prevent development of obesity-associated comorbidities.