Metabolic syndrome (MetS) is a cluster of metabolic abnormalities with insulin resistance (IR) as a major component. It has been recently questioned whether MetS and its related components are associated with functional and morphological alterations of the thyroid gland. The aim of our study is to examine thyroid volume and nodule prevalence in a case-control study of patients with MetS in a mild-to-moderate iodine-deficient area. Two hundred and seventy-eight patients with MetS were randomly matched for age, gender, and smoking habits with 261 subjects without MetS. Serum TSH, free tri-iodothyronine and thyroxine, and the level of IR, which was estimated by the homeostasis model assessment for IR, as well as other MetS parameters were evaluated. Thyroid ultrasonography was performed in all subjects. All subjects with thyroid nodules >1 cm were offered to undergo thyroid fine needle aspiration biopsy. TSH was significantly positively correlated with the presence of MetS diagnosis. There was no association between free thyroid hormone levels and MetS and its related components. Mean thyroid volume was significantly higher in patients with MetS than in controls (17.5 + or - 5.5 vs 12.2 + or - 4.2 ml, P<0.0001). Also the percentage of patients with thyroid nodules was significantly higher in patients with MetS (50.4 vs 14.6%, P<0.0001). Subjects were also divided into two groups according to the presence of IR. The group of subjects with IR had increased thyroid volume and nodule formation. The odds ratio for the development of thyroid nodule in the presence of IR was 3.2. TSH as well as all MetS components were found to be independent predictors for thyroid volume increase. IR but not TSH was found to be correlated with thyroid nodule formation. Thyroid cancer was diagnosed in 3 out of 38 patients with MetS who agreed to have a biopsy (7.9%). None of the subjects in the control group was diagnosed to have thyroid cancer. The results suggest that patients with MetS have significantly increased thyroid volume and nodule prevalence. Multivariate regression analysis model demonstrated that the presence of IR contributed substantially to this increased risk. Our data provide the first evidence that IR is an independent risk factor for nodule formation in an iodine-deficient environment.