Metabolic syndrome (MS) is a multi-factorial disorder with insulin resistance as a major characteristic. Adiponectin, an adipocyte derived cytokine, can regulate glucose levels and lipid homeostasis by its insulin sensitizer properties. Low circulating levels of serum adiponectin has been reported as a risk factor for the development of MS. The aim of this case control study was to investigate the association of serum adiponectin concentration, insulin resistance and various risk factors with MS among Tunisian participants. We designed a case-control study involving 100 patients with MS (84 females and 16 males, mean age 54±11 years) and 100 healthy controls (60 females and 40 males, mean age 51±10 years). Serum total cholesterol and triglyceride were determined by enzymatic methods. Insulin resistance was calculated using the homeostasis model assessment (HOMA-IR) = fasting insulin (uU/ml) x fasting plasma glucose (mmol/l)/22.5 and serum adiponectin levels were measured by enzyme-linked immunosorbent assay. Interestingly, 72% of the subjects with MS had high blood pressure. Compared with controls, patients had significantly higher levels of triglycerides (1.64±0.88 mmol /l; 1.07±0.43 mmol/l; p=0.03) and lower levels of high-density lipoprotein cholesterol (1.26±0.41 mmol/l; 1.58±0.30 mmol/l; p=0.04). In addition, there was a significant difference in serum adiponectin levels between the subjects with MS and controls (13.96±5.23 µg/ml; 22.24±9.07 µg/ml; p=0.006) and the mean levels of HOMA-IR were 5.23±3.52 and 1.83±0.93 for patients and controls, respectively. In conclusion, hypoadiponectinemia and insulin resistance represent risk factors for MS development.