BACKGROUND Metformin was found to reduce elevated serum thyrotropin levels. No previous study has compared the effect of this drug on serum levels of thyrotropin and thyroid hormones between men and women. METHODS The study included 23 women and 12 men with subclinical hypothyroidism, who because of coexisting diabetes or impaired fasting glucose were treated with metformin (1.7-3.0g daily). Fasting plasma glucose levels, the homeostatic model assessment 1 of insulin resistance ratio (HOMA1-IR), glycated hemoglobin, serum levels of thyrotropin, free and total thyroid hormones and prolactin, as well as thyroid peroxidase and thyroglobulin antibodies were assessed at baseline and after 4 months of metformin treatment. RESULTS Baseline serum levels of thyrotropin, free thyroxine and free triiodothyronine, as well as a percentage of patients with positive thyroid peroxidase and thyroglobulin antibodies were comparable in both sexes. Metformin treatment reduced plasma glucose and insulin resistance, irrespective of the gender. However, only in women, metformin decreased serum thyrotropin levels. Neither in men nor in women, metformin affected serum levels of thyroid hormone and prolactin, as well as in the subgroups of patients with thyroiditis thyroid antibody titers. CONCLUSIONS The obtained results suggest that sex may determine the effect of metformin on hypothalamic-pituitary-thyroid axis activity.