Objectives: Non-diabetic first-degree relatives (FDR) of type 2 diabetes mellitus (T2DM) patients have been reported to have relatively higher insulin resistance and inflammatory markers compared to population without family history of T2DM. We investigated whether healthy FDR T2DM of Indonesian males living in urban area are more susceptible to the adverse effects of high-fat diet (HFD) than non-FDR subjects. Methods: Twentyseven normoglycemic and normotensive FDR males and 28 ageand-body-mass-index-(BMI)-matched healthy non-FDR males underwent a 5-days HFD challenge. Dietary intake before and after HFD were collected by 24-hours food recall. Metabolic profiles and plasma cytokine levels were assessed before and after the HFD intervention. Results: Within similar BMI profile between groups, FDR subjects showed significantly bigger waist circumference (p=0.001) and higher triglyceride (p=0,03) than those of non-FDR. Despite similar HOMA-IR and IL-6 responses to 5-days HFD, significant increase of plasma TNF-α/IL-10 ratio found in FDR subjects, while in contrary, TNF-α/IL-10 ratio significantly decreased in non-FDR group (p<0.001), resulting an OR of 7.1 (95% CI 2.2-23.4) for FDR to develop elevated plasma TNF-α/IL-10 ratio in response to HFD. The tendency was as high as 24.8 (95% CI 2.3-262.6) in FDR subjects with BMI ≥25 compared to the corresponding non-FDR subjects. Conclusions: High-fat diet induced insulin resistance and increase of IL-6 plasma in healthy adult Indonesian males. Immune response polarization favouring proinflammatory environment was predominantly occurred in FDR subjects when compared to those of nonFDR subjects. Alteration of lipid accumulation was highly likely contributed to greater HFD-inflammation effects on FDR than non-FDR subjects.><0.001), resulting an OR of 7.1 (95% CI 2.2-23.4) for FDR to develop elevated plasma TNF-α/IL-10 ratio in response to HFD. The tendency was as high as 24.8 (95% CI 2.3-262.6) in FDR subjects with BMI ≥25 compared to the corresponding non-FDR subjects. Conclusions: High-fat diet induced insulin resistance and increase of IL-6 plasma in healthy adult Indonesian males. Immune response polarization favouring proinflammatory environment was predominantly occurred in FDR subjects when compared to those of nonFDR subjects. Alteration of lipid accumulation was highly likely contributed to greater HFD-inflammation effects on FDR than non-FDR subjects.