OBJECTIVE This study investigated the effects of levothyroxine replacement therapy on insulin resistance, lipid profile, and thyroid function in patients with untreated primary hypothyroidism. 105 patients with hypothyroidism with indication for levothyroxine replacement were enrolled in the present study. Insulin, fasting blood glucose and lipid profile were assessed at the beginning of diagnosis and three months after levothyroxine replacement. Insulin resistance was calculated by hemostasis model assessment of insulin resistance (HOMA-IR) and quantitative insulin sensitivity check index (QUICKI). RESULTS Our data revealed a significant reduction in body mass index (27.18 ± 4.27 versus 26.81 ± 4.18 kg/m2, p = 0.028), cholesterol (199.79 ± 37.61 versus 178.10 ± 32.25 mg/dl, p < 0.001), triglyceride (160.41 ± 71.86 versus 146 ± 61.11 mg/dl, p = 0.012), low density lipoprotein-cholesterol (123.54 ± 30.7 versus 107.08 ± 26.98 mg/dl, p < 0.001), fasting insulin (8.91 ± 3.92 versus 8.05 ± 2.65 mIU/l, p < 0.001), and thyroid stimulating hormone (47.47 ± 3.4 versus 2.22 ± 1.84 µIU/ml, p < 0.001) levels before and after drug intervention. However, no statistical differences were observed in HOMA-IR, QUICKI, and high density lipoprotein-cholesterol. In conclusion, in patients with untreated primary hypothyroidism, levothyroxine replacement therapy based on HOMA-IR and QUICKI did not improve insulin resistance; however, lipid profile was significantly improved following levothyroxine administration. BACKGROUND This study was registered in the Iranian Registry of Clinical Trials (IRCT) with ID number: IRCT20130610013612N10 on the date 2019-09-02.