Objective: The aim of the study was to evaluate the expression of tumor necrosis factor (TNF)-a protein in the subcutaneous and visceral adipose tissue in correlation with adipocyte cell volume, serum TNFa, soluble TNF-receptor-2 (sTNFR-2) and indirect parameters of insulin resistance in overweight/obese and lean healthy persons. Design: A cross-sectional case-control study was used. Patients: Twenty-eight overweight/obese probands with normal glucose tolerance (BMI . 27 kg/m 2 ) and 15 lean people (BMI , 25 kg/m 2 ), all of them undergoing planned surgical operation, participated in the study. Methods: Two to four grams of subcutaneous and visceral adipose tissue were removed and studied using semi-quantitative immunohistochemical staining of the TNF-a protein. Serum TNF-a, sTNFR-2 (ELISA) and fasting C-peptide (RIA) were measured. Results: TNF-a protein was expressed in adipocytes of both depots. The expression was evaluated visually and found to be greater in the obese patients. Significantly higher serum TNF-a (5.58^0.87 pg/ml vs 4.21^0.55, mean^S.D., P , 0.01, Mann -Whitney) and sTNFR-2 levels (7.84^3.56 ng/ml vs 4.59^1.35, P ¼ 0.005) were found in the obese subgroup in correlation with the fasting C-peptide level (r ¼ 0.49, P ¼ 0.003; and r ¼ 0.74, P ¼ 0.001) and the C-peptide/ blood glucose ratio (r ¼ 0.47, Spearman, P ¼ 0.005; and r ¼ 0.70, P ¼ 0.001). The cell volume of both adipocyte depots was found to have a significant positive correlation with serum TNF-a and sTNFR-2 levels in the total group of patients (subcutaneous: r ¼ 0.52, P ¼ 0.0003; r ¼ 0.69, P , 0.0001; visceral: r ¼ 0.65, P , 0.0001; r ¼ 0.63, P , 0.0001) and in both subgroups. Conclusions: Adipocyte cell volume of both the subcutaneous and visceral fat depots may be determinants of TNF-a, sTNFR-2 production and obesity-linked insulin resistance.