AIMS: A thyrotropin(TSH)-lowering effect of metformin therapy has been recently reported in patients with type 2 diabetes (T2D) and hypothyroidism. We aimed to evaluate the interplay between metformin therapy and serum TSH concentrations in a group of patients with T2D and normal thyroid function. PATIENTS AND METHODS: Eight hundred and twenty-eight euthyroid patients with T2D (53% females, mean age 65.9 yr, median duration of diabetes 10 yr) were retrospectively evaluated. There were 250 patients on metformin treatment (30.2%). Serum concentrations of TSH were measured in all subjects. RESULTS: Patients on metformin treatment exhibited significantly higher TSH levels (1.63 [1.11-2.24] mU/l) than those found in patients without metformin (1.40 [1.01-2.24]mU/l, P=0.009). We found no significant differences in TSH levels in patients who were on therapy with other oral antidiabetics, antihypertensive drugs or hypolipidemic agents in relation to subjects not taking these drugs. Serum TSH was significantly related to gender, body mass index, hyperlipidaemia, and the presence of goitre and diabetic macroangiopathy. In multiple regression analysis with TSH as dependent variable goitre was negatively related to TSH values. Metformin therapy was a non-significant variable in this model. CONCLUSION: In summary, this is the first survey analyzing the relationship between metformin and thyroid function in a large cohort of diabetic patients. Our data do not support the presence of an independent and significant relationship between TSH values and metformin treatment in euthyroid T2D patients. © 2012 Blackwell Publishing Ltd.