Familial combined hyperlipidemia (FCHL) is a genetic disorder of lipid metabolism associated with insulin resistance and abnormalities in fatty acid metabolism whose underlying mechanisms are largely unknown. Perturbations in the TNFα/TNF-R pathway may play a role in these abnormalities.We determined plasma levels of TNFα and sTNF-R p75 in 85 FCHL patients (TC 245±45 mg/dl; TG 260±148 mg/dl; apoB 148±37 mg/dl) and in 29 age- and sex-matched normolipemic relatives (NL) (TC 187±22.8 mg/dl; TG 115±37 mg/dl; apoB 106±16 mg/dl). Thirty-four normolipemic subjects (TC 180±34 mg/dl; TG 107±42 mg/dl; apoB 95±22 mg/dl) were also included as unrelated controls (NC). Plasma free fatty acids (NEFA) were also measured and insulin sensitivity was evaluated by HOMA. Levels of sTNF-R p75 were significantly reduced in FCHL compared to NL (2.30±0.55 ng/ml vs. 2.64±0.88 ng/ml, p<0.05) but not compared to NC (2.35±0.68 ng/ml). HOMA values were comparable in all groups and did not show any relation with plasma levels of sTNF-R p75. Logistic analysis demonstrated that a low concentration of sTNF-R p75 was an independent predictor of the affected status within FCHL families, but this role was no longer evident when FCHL patients were compared to NC. In FCHL, age (p<0.001) was positively, and TG (p=0.029) and HDL-C (p=0.025) were negatively correlated with plasma concentrations of sTNF-R p75. In the other groups, age (in NL) and non-HDL-C (in NC) were significantly correlated with sTNF-R p75.Although our data do not support a causative role of TNFα/TNF-R alterations in FCHL, they confirm that variation in TNF-R shedding may influence lipid phenotypic expression in FCHL families.