Grape seed oil (GSO) is reported to improve oxidative stress and lipid profile. However, the ameliorating effect of GSO on inflammation and insulin resistance has not being noticed so far. We aimed to examine the effects of GSO consumption on inflammation and insulin resistance in overweight or obese females. The subjects (n = 44) were randomly assigned into intervention group as "GSO" (consuming 15% of energy from GSO) and control group as sunflower oil "SFO" (consuming 15% of energy from SFO) through a weight loss diet for 8 weeks. Anthropometric measurements, dietary recall and fasting serum glucose, insulin, high sensitive C-reactive protein (hs-CRP) and tumor necrosis factor-alpha (TNF-α) were assessed before and after the intervention. Homeostatic model assessment of insulin resistance (HOMA-IR) scores, hs-CRP and TNF-α decreased in the GSO group. The hs-CRP was lower in GSO than the SFO group (p < 0.03). GSO consumption seems to improve inflammatory condition and insulin resistance in overweight/obese women.