Tumor necrosis factor-alpha (TNFalpha) and its soluble receptor 2 (TNFR2) are expressed in adipose tissue and are possibly involved in the pathogenesis of insulin resistance. Information about serum levels of TNFR2 in human obesity, especially the possible role of genetic factors and body fat distribution, is scanty. We measured serum TNFalpha and soluble TNFR2 concentrations in 23 identical twin pairs who had an average 18-kg intrapair difference in body weight. The mean TNFalpha concentration was 44.1 ng/L in obese and 34.2 ng/L in lean cotwins (P = 0.051). The respective values for TNFR2 were 1,989 and 1,840 ng/L (P = 0.004). The intrapair difference in TNFR2 level correlated positively (r-value always > or = 0.56; P < or = 0.01) with intrapair differences in body mass index, percent body fat, and abdominal sc fat area (assessed by magnetic resonance imaging), but not with differences in visceral fat area, glucose or insulin areas under the curve, or insulin sensitivity index in the oral glucose tolerance test. The intraclass correlation for TNFR2 was 0.67, and the genetic variation in circulating TNFR2 level was almost 6-fold higher than the variation due to obesity. We conclude that the soluble TNFR2 concentration is determined by both genetic factors and adiposity, especially sc fat. Measurement of circulating TNFR2 does not seem to be useful in identifying obese individuals who are insulin resistant.