A hypocaloric diet and regular physical exercise are recognized as effective non-pharmacological interventions to reduce body fat mass and mange cardiovascular disease. In this context, resistance training with or without a concomitant hypocaloric diet is gaining acceptance as a useful tool in weight reduction interventions and in cardiovascular disease therapy. The purpose of this study was to ascertain the effects of a weight loss diet (WL) with a caloric restriction of 500 kcal/day alone or combined with a 16 week supervised whole body progresive resistance training (RT) of two sessions/week (WL+RT), on weight, body composition, insulin sensitivity and lipid profile, in thirty-four obese (BMI: 30¿40 kg/m2) women, aged 40¿60 year with hypercholesterolemia (CT >240 mg/dl). Moreover, we also evaluate the interaction of a higher protein vs. a lower protein diet, with or without a concomitant progressive resistance training program, on lipoprotein profile. The 16 weeks of intervention (WL and WL+RT groups) were accompanied by a significant decrease in body weight, BMI, waist circumference, abdominal fat and thigh subcutaneous fat, not significant differences being observed between both groups. Moreover, a significant loss in thigh muscle mass (measured by magnetic resonance) was observed only in the WL group. Of note, a weight-loss diet alone or combined with a RT program induced different regional changes in visceral and subcutaneous adipose tissue volume distribution patterns. At the same time, changes in association patterns between variables of the glucose metabolism and lipid profile and the abdominal fat depots at different discal levels were observed from pre- to post- intervention. On the other hand, while the lipid profile showed no modification in the WL group, the hypercholesterolemic women of the WL+RT group experienced a significant decrease in total cholesterol and LDL-C. Summary up, in obese women a 16-week combined RT program and weight-loss diet were accompanied by significant improvements in cardiometabolic profile in spite of a significant decrease of circulating adiponectin. Finally, we found an interaction between the protein content of the energy-restricted diet and the resistance training on the circulating levels of LDL-C. When RT was combined with a lower protein- hypocaloric diet (< 22% of the daily calorie intake as protein) a greater effect was observed, whereas a higher daily protein intake (≥ 22% of the daily calorie intake as protein group) did not show any additional effect on lipid profile.