Intervention studies on the Mediterranean Diet (MedDiet) have often led to weight loss, which may have contributed to the purported anti‐inflammatory effects of the MedDiet. To investigate the impact of the MedDiet consumed under controlled feeding conditions before (−WL) and after weight loss (+WL) on markers of inflammation in men with metabolic syndrome (MetS).

Subjects (N = 26, male, 24–65 years) with MetS first consumed a North American control diet for 5 weeks followed by a MedDiet for 5 weeks both in isocaloric feeding conditions. After a 20‐week weight loss period in free‐living conditions (10 ± 3% reduction in body weight, P < 0.01), participants consumed the MedDiet again under isocaloric‐controlled feeding condition for 5 weeks.

MedDiet − WL significantly reduced plasma C‐reactive protein (CRP) concentrations (−26.1%, P = 0.02) and an arbitrary inflammatory score (−9.9%, P = 0.01) that included CRP, interleukin‐6 (IL‐6), IL‐18, and tumor necrosis factor‐α (TNF‐α) compared with the control diet. The MedDiet + WL significantly reduced plasma IL‐6 (−20.7%) and IL‐18 (−15.6%, both P ≤ 0.02) concentrations compared with the control diet but had no further significant impact on plasma CRP concentration. Participants with a reduction in waist circumference ≥8.5 cm after MedDiet + WL showed significantly greater reductions in inflammation markers than those with a change in waist circumference <8.5 cm.

Thus, consuming MedDiet even in the absence of weight loss significantly reduces inflammation. However, the degree of waist circumference reduction with weight loss magnifies the impact of the MedDiet on other markers of inflammation associated with MetS in men.