OBJECTIVE: To evaluate the effects of acute and daily consumption of high-oleic peanuts (HOP) on inflammation and glucose homeostasis in overweight/obese men. METHODS: In a 4-week randomized clinical trial, males with body mass index of 29.8 ± 2.3 kg/m(2) and aged 18-50 years were assigned to the groups: control (CT, n = 22); conventional peanuts (CVP, n = 22); or HOP (n = 21). They followed a hypocaloric-diet with or without 56 g/day of CVP or HOP. Main outcomes were changes in fasting blood biomarkers and postprandial insulin, glucose, tumor necrosis factor-alfa (TNF-α), and interleukin-10 (IL-10) responses after acute peanut intake. RESULTS: At baseline, HOP showed significantly lower postprandial responses of glucose, insulin, and TNF-α than CVP and CT. Changes in fasting blood biomarkers did not differ between groups after the 4-week intervention. However, within groups, total cholesterol decreased in CT, and all groups reduced High-density lipoprotein (HDL-c). Triglycerides were reduced in HOP and CVP. IL-10 increased significantly in all groups while only the CT and CVP showed increased TNF-α after intervention. CONCLUSION: Acute high-oleic peanut consumption leads to stronger moderation of postprandial glucose, insulin, and TNF-α concentrations than CVP and control meal intake. Whether daily intake of high-oleic peanuts has additional benefits to CVP remains uncertain.