Recent evidences suggest that modulation of vascular structure by matrix metalloproteinases (MMPs) could be a main determinant of acute cardiovascular events in high-risk subjects. The authors consecutively selected 46 subjects affected by familial combined hyperlipidemia (FCH), 44 by metabolic syndrome (MS), 44 by FCH and MS, and 40 healthy subjects. All these subjects were firstly diagnosed and not treated with lipid-lowering, antihypertensive, or antidiabetic drugs. A 12-h fasting blood sample was obtained from each patient, and plasma levels of MMP-2 and MMP-9 were measured together with their tissue inhibitors and a full set of laboratory cardiovascular disease markers. MMP-2 plasma levels were not significantly different among the considered groups. MMP-9, tissue inhibitor of MMP (TIMP)-1, and TIMP-2 are significantly higher in FCH (p < .001) and MS (p < .001) patients than in healthy controls, and they are also higher in MS patients than in FCH ones (p < .001). TIMP-1 (p < .001) and TIMP-2 (p < .001), but not MMP-9, are also significantly higher in subjects with MS associated to FCH than in patients with MS alone. No specific correlation among MMPs, TIMPs, and the other studied parameters has been observed in the whole sample and in the four above-defined subgroups. MMP-9, TIMP-1, and TIMP-2 plasma levels could be significant determinant and/or diagnostic markers of MS but not of FCH. However, the superposition of MS on FCH further increases the plasma level of these parameters. The prognostic value of this observation has to be evaluated.