No study has yet examined how weight loss specifically modifies the impact of the Mediterranean diet (MedDiet) on plasma cell adhesion molecules (CAM) in men with the metabolic syndrome (MetS). Therefore, this study examined the impact of the MedDiet consumed under controlled feeding conditions, with and without weight loss, on plasma CAM concentrations in men with the MetS. The diet of 26 men (age 24-62 years) with the MetS was first standardized to a North American control diet for 5 weeks followed by a 5-week MedDiet, both under weight-maintaining isocaloric feeding conditions. Participants then underwent a 20-week caloric restriction period that led to a 10.2 ± 2.9% reduction in body weight (p \ 0.01), followed by the consumption of an isocaloric weight stable MedDiet for 5 weeks. All foods including red wine were provided during the isocaloric phases of the study. There was no change in the average concentrations of any of the CAM after the MedDiet without weight loss. The MedDiet combined with weight loss reduced plasma CAM concentrations by 10.9% (p \ 0.01) compared with the control diet and by 6.8% (p = 0.068) compared with the MedDiet without weight loss. These data suggest that weight loss is required for the MedDiet to improve plasma CAM concentrations over a short period of time in men with the MetS. ClinicalTrial.gov registration number: NCT00988650.