Calorie restriction without malnutrition is likely to improve cardiovascular risk factors. The aim of this study was to investigate calorie restriction on markers of cardiometabolic risk in overweight/obese adults with cardiovascular risk factors. In a parallel controlled trial, patients with overweight or obesity and one or more cardiovascular risk factor were randomized to a modest reduced-calorie diet (75% of the total calculated energy requirements) or control (no calorie restriction) groups and followed up for two months. Body weight, dietary intake, fasting plasma levels of C-reactive protein (CRP), monocyte chemoattractant protein-1 (MCP-1), intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), brain-derived neurotrophic factor (BDNF), neuropeptide Y (NPY), lipids, and glycemic factors were measured at baseline, and after two months. The differences were analyzed with analysis of covariance (ANCOVA). Sixty-six participants (33 in each group) completed the study. Body weight changed in the reduced-calorie diet group (- 3.05 ± 2.65 kg), and blood pressure was improved (systolic -6.96 ± 12.04 and diastolic - 3.90 ± 8.97 mmHg). The reduced-calorie diet improved plasma ICAM-1 (change from baseline - 0.45 ± 1.99 ng/mL, P = 0.033, ANCOVA), MCP-1 (change from baseline - 0.50 pg/mL, P = 0.011, ANCOVA), low-density lipoprotein cholesterol (change from baseline - 9.35 ± 19.61 mg/dL, P < 0.001, ANCOVA), and triglyceride (change from baseline -33.66 ± 49.08, P = 0.001, ANCOVA), but BDNF, NPY, and other cardiometabolic factors were not different. In overweight/obese subjects with cardiovascular risk factors which have been under medical treatment with risk-reducing medications, a modest weight loss induced by a reduced-calorie diet improved lipid profile, blood pressure, and reduced ICAM-1 and MCP-1 levels but had no effect on plasma BDNF or glycemic factors.